SUBSTITUTED N-(lH-INDAZOL-4-YL)IMIDAZO[l,2-a]PYRIDINE-3-CARBOXAMIDE COMPOUNDS AS TYPE III RECEPTOR TYROSINE KINASE INHIBITORS

ABSTRACT

Compounds of Formula I: 
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable salts thereof in which R 1 , R 2 , R 3 , R 4 , R 5  and R 6  have the meanings given in the specification, are inhibitors of cFMS and are useful in the treatment of fibrosis, bone-related diseases, cancer, autoimmune disorders, inflammatory diseases, cardiovascular diseases, pain and burns in a mammal.

The present invention relates to novel compounds, to pharmaceuticalcompositions comprising the compounds, to processes for making thecompounds, and to the use of the compounds in therapy. Moreparticularly, it relates to certain substitutedN-(1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide compounds whichare inhibitors of type III receptor tyrosine kinases such as PDGFRand/or cFMS and/or cKIT, which are useful in the treatment of fibrosis,bone-related diseases, cancer, autoimmune disorders, inflammatorydiseases, cardiovascular diseases, pain and burns.

PDGFR is expressed on early stem cells, mast cells, myeloid cells,mesenchymal cells, and smooth muscles cells. PDGFR-β has been implicatedin myeloid leukemias. Recently, it was shown that activating mutationsin PDGFR-α kinase domain are present in gastrointestinal stromal tumors(GIST) (Wong et al., 2007, Histopathology 51(6): 758-762).

PDGFR has been shown to be a potent mitogen for myofibroblast formation,a signature of fibrotic conditions and implicated in the progression offibrosis (Bonner, J. et al., 1998, American Journal Physiology 274(1Pt1): L72-L80).

In addition, blockade of PDGF signaling has been demonstrated to reducethe development of fibrosis in various experimental models (Yoshiji, etal., 2006, Int. J. Mol. Med. 17:899-904). Imatinib, for example, a knowninhibitor of PDGF signaling, has demonstrated anti-fibrotic activity inseveral animal models of fibrosis (Akhmetshina, A., et al., 2009,Arthritis Rheumatism 60(1): 219-224; Vuorinen, K., et al., 2007,Experimental Lung Research 33(7): 357-373; Aono, Y., et al., 2005,American Journal Respiratory Critical Care Medicine 171(11): 1279-1285).There are multiple case reports of patients with fibrotic conditionsbenefiting from treatment with Imatinib (Kay, J., et al., 2008,Arthritis Rheumatism 58(8): 2543-2548; Distler J., et al., 2008,Arthritis Rheumatism 58(8): 2538-2542; Hirose, Y., et al., 2002International Journal Hematology 76(4): 349-353). Imatinib recentlycompleted a randomized, placebo-controlled phase II study in patientswith idiopathic pulmonary fibrosis (IPF).

Macrophage colony-stimulating factor-1 receptor (CSF-1R), a tyrosinereceptor kinase also known as cFMS, is the receptor for colonystimulating factor-1 (CSF-1), also known as M-CSF. CSF-1 is an importantgrowth factor for bone progenitor cells, monocytes, macrophages, andcells of macrophage lineage such as osteoclasts and dendritic cells.Binding of CSF-1 to the cFMS extracellular domain induces cFMSdimerization and trans-autophosphorylation of the intracellular cFMSkinase domain. Once phosphorylated, cFMS serves as a docking site forseveral cytoplasmic signaling molecules, the activation of which leadsto de novo gene expression and proliferation. Robust expression of cFMSis restricted to monocytes, tissue macrophages, and osteoclasts, andtherefore cFMS inhibitors may be useful in treating diseases whereosteoclasts, dendritic cells and macrophages are pathogenic, such asautoimmune/inflammatory diseases, cancer and bone-related diseases.

Bone is a dynamic tissue, subject to a constant remodeling process thatoperates to maintain skeletal strength and health. This remodelingprocess entails two phases: an osteolysis phase and an osteogenesisphase. In osteolysis, osteoclast cells invade bone and erode it byreleasing acids and enzymes that dissolve collagen and minerals. Thiscreates a small cavity in the bone. In osteogenesis, osteoblast cellsdeposit new collagen and minerals into the cavity. When osteolysis andosteogenesis are in balance, no net change in bone mass results.However, in certain disease states, osteolysis is more active thanosteogenesis, resulting in a net loss of bone.

One particularly serious cause of localized excessive osteolysis iscancer metastasis to bone. Cancer cells often secrete factors, such asM-CSF, that promote osteoclast development and activity. When suchcancers establish themselves in bone, they promote extensive osteolyticdamage and can result in, for example, bone fracture and spinalcompression. Such tumor-associated osteolysis coincides with many typesof malignancies, including hematological malignancies (e.g., myeloma andlymphoma) and solid tumors (e.g., breast, prostate, lung, renal andthyroid). Accordingly, there remains a need for therapies that reduce ordelay complications which arise from the spread of cancer to the bone.

When excessive osteolysis occurs throughout broad areas of the skeleton,it falls under the generic description osteoporosis. Common types ofosteoporosis include age-related, post-menopausal, treatment-inducedbone loss (e.g., as a result of treatment with glucocorticoids,aromatase inhibitors, or anti-androgen therapy), diabetes-associated anddisuse osteoporosis. In the United States alone, millions of individualssuffer from the disease and its attendant pain, deformities anddebilitating fractures.

Osteoclasts are multinucleated cells that are derived from monocyticprecursors and operate under the control of numerous cytokines andgrowth factors. Differentiation of the monocytic precursors intoosteoclasts is a complex process that requires both M-CSF and RANKL(receptor activator of the NF-kappa B ligand). Inhibiting osteoclastdevelopment and function is a desirable approach to treating excessiveosteolysis. However, the currently available substances that do so havelimited utility, and often cause significant side effects. Thus, acontinuing need exists for effective and practical treatments forexcessive osteolytic conditions.

Macrophages, which are related to osteoclasts, play an important role ininflammatory disease, cancer and bone disorders. For example,macrophages, which are related to osteoclasts, are a major component ofthe host cellular response to cancers, and can contribute to tumorgrowth. In particular, macrophages, as well as tumor cells, secreteM-CSF, a key cytokine for development of osteoclasts from monocyteprecursors. Macrophages, as well as monocytes and some tumor cells, alsoexpress M-CSF receptors.

Solid tumors comprise a number of cell types, including macrophages.These tumor-associated macrophages (TAMs) are believed to play a numberof roles to promote tumor progression and metastasis (Pollard, J. W.,Nat. Rev. Cancer, 2004, 4:71; Lewis, C. E. and Pollard, J. W., CancerRes., 2006, 66:605). Upon recruitment to the tumor environment,macrophages release factors involved in the growth and motility of tumorcells. Monocyte/macrophage development and proliferation depends uponthe signaling pathway of CSF-1R and its ligand CSF-1. Recent depletionstudies in cancer models showed a role for M-CSF in promoting tumorgrowth and progression to metastasis (Chitu, V. and Stanley, E. R.,Curr. Opin. Immunol., 2006, 18:39-48; Pollard, J. W., Nature Rev.Cancer, 2004, 80:59-65; Paulus, P., et al., Cancer Res. 2006,66:4349-4356). Inhibition of this pathway therefore could reduce TAMlevels, leading to multiple effects on tumor types in which macrophageshave a significant presence.

Macrophages are also a predominant source of tumor necrosis factor (TNF)and interleukin-1 (IL-1) in the destructive pannus of rheumatoidarthritis. TNF and IL-1 activate stromal expression of hematopoieticfactors including CSF-1. In turn, CSF-1 recruits monocytes and promotesmacrophage survival, functional activation, and in some settings,proliferation. Thus, TNF and CSF-1 interact in a perpetuating cycle thatleads to inflammation and joint destruction. Macrophage numbers are alsoelevated in atherosclerotic plaque (Arch. Pathol. Lab. Med. 1985, 109:445-449) where they are thought to contribute to disease progression.

Inflammatory mechanisms are also believed to play an important role inhyperalgesia resulting from nerve injury. Nerve damage can stimulatemacrophage infiltration and increase the number of activated T cells(Abbadie, C., 2005, Trends Immunol. 26(1):529-534). Under theseconditions, neuroinflammatory and immune responses contribute as much tothe development and maintenance of pain as the initial damage itself.The role of circulating monocytes/macrophages in the development ofneuropathic hyperalgesia and Wallerian degeneration due to partial nerveinjury was confirmed in an animal model (Liu et al., Pain, 2000, 86:25-32) in which macrophages were depleted following sciatic nerveligation. In this study, treatment of nerve-injured rats withliposome-encapsulated Cl₂MDP (dicloromethylene diphosphonate), which isreported to effectively reduce the number of macrophages at the site ofnerve transaction, alleviated thermal hyperalgesia and reduceddegeneration of both myelinated and unmyelinated axons. In addition, inmany instances neuropathic pain is associated with nerve inflammation(neuritis) in the absence of nerve injury. Based on an animal model ofneuritis (Tal M., Curr. Rev. Pain 1999, 3(6):440-446), it has beensuggested that there is a role for some cytokines in nociception andhyperalgesia by evoking peripheral sensitization, in which trauma andclassical tissue inflammation are not seen. Thus, macrophage depletionby administration of a cFMS inhibitor could have clinical potential intreatment or prevention of neuropathic pain, either as a result of nerveinjury and in the absence of nerve injury.

Several classes of small molecule inhibitors of cFMS said to be usefulfor treating cancer, autoimmune and inflammatory diseases are known(Huang, H. et al., J. Med. Chem, 2009, 52, 1081-1099; Scott, D. A. etal., Bioorg. & Med. Chem. Lett., 2009, 19, 697-700).

C-KIT receptor, also called CD117, is expressed on the surface ofvarious cell types, including hematopoietic stem cells. This cytokinereceptor is associated with certain forms of gastric cancer (Novak, C.et al., 2010 Mini Rev. Med. Chem. 10(7): 624-634). Imatinib andSunitinib are both inhibitors of cKIT and are generally effective intreatment of patients with GIST. Eventually, however, patients developresistance to both agents and alternative options remain limited.

There is evidence that cKIT and mast cells play a detrimental role insettings of fibrosis. For example, mast cells are concentrated in thelesional small-airway sub-epithelium in obliterative bronchiolitis(Fuehrer, N. et al., 2009, Archives Pathology Laboratory Medicine133(9): 1420-1425). In addition, there is evidence that cKIT positivecells are involved in the pathogenesis of ureteropelvic junctionobstruction (Ozel, S. et al., 2009, Journal Pediatric Urology, August27^(th)).

Pulmonary arterial hypertension (PAH) involves the increase of bloodpressure in the pulmonary artery and there is evidence thatdysfunctional endothelial progenitors over-expressing cKIT contribute tothe pathology of PAH (Toshner, M., et al., 2009, American JournalCritical Care Medicine 180(8): 780-787).

SUMMARY OF THE INVENTION

It has now been found that certain substitutedN-(1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide compounds areinhibitors of type III receptor tyrosine kinases such as PDGFR, cFMSand/or cKIT, and may be useful for treating disorders and diseasessensitive to inhibition of these kinases.

Accordingly, one embodiment of this invention provides a compound of thegeneral Formula I:

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴,R⁵ and R⁶ are as defined herein.

In another aspect of the invention, there are provided pharmaceuticalcompositions comprising compounds of Formula I and a carrier, diluent orexcipient.

In another aspect of the invention, there is provided a method ofinhibiting type III receptor tyrosine kinases such as PGDFR, cFMS and/orcKIT in a mammal comprising administering to said mammal in need thereofa therapeutically effective amount of a compound of Formula I.

In another aspect of the invention, there is provided a method fortreating a disease or disorder selected from fibrosis, bone-relateddiseases, cancer, autoimmune disorders, inflammatory diseases,cardiovascular diseases, pain and burns in a mammal, which comprisesadministering to said mammal in need thereof a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof.

In another aspect of the invention, there is provided a method fortreating a disease or disorder selected from fibrosis, bone-relateddiseases, cancer, autoimmune disorders, inflammatory diseases,cardiovascular diseases and pain in a mammal, which comprisesadministering to said mammal in need thereof a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof.

In another aspect of the invention, there is provided a use of acompound of Formula I in the manufacture of a medicament for thetreatment of a disease or disorder selected from fibrosis, bone-relateddiseases, cancer, autoimmune disorders, inflammatory diseases,cardiovascular diseases, pain and burns in a mammal, which comprisesadministering to said mammal in need thereof a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof.

In another aspect of the invention, there is provided a use of acompound of Formula I in the manufacture of a medicament for thetreatment of a disease or disorder selected from fibrosis, bone-relateddiseases, cancer, autoimmune disorders, inflammatory diseases,cardiovascular diseases and pain in a mammal, which comprisesadministering to said mammal in need thereof a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof.

In another aspect of the invention, there is provided a use of acompound of Formula I in the treatment of a disease or disorder selectedfrom fibrosis, bone-related diseases, cancer, autoimmune disorders,inflammatory diseases, cardiovascular diseases and pain in a mammal.

In another aspect of the invention, there is provided a compound ofFormula I for use in the treatment of a disease or disorder selectedfrom fibrosis, bone-related diseases, cancer, autoimmune disorders,inflammatory diseases, cardiovascular diseases. pain and burns in amammal.

In another aspect of the invention, there is provided a compound ofFormula I for use in the treatment of a disease or disorder selectedfrom fibrosis, bone-related diseases, cancer, autoimmune disorders,inflammatory diseases, cardiovascular diseases and pain in a mammal.

Another aspect provides intermediates for preparing compounds of FormulaI. In one embodiment, certain compounds of Formula I may be used asintermediates for the preparation of other compounds of Formula I.

Another aspect includes processes for preparing, methods of separation,and methods of purification of the compounds described herein.

DETAILED DESCRIPTION OF THE INVENTION

Accordingly to one embodiment, this invention provides a compound of thegeneral Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is hetAr¹(CH₂)_(m)—, hetAr²CH₂—, hetAr³CH₂—, (3-6C cycloalkyl)-CH₂—,hetCyc¹CH₂—, Ar¹(CH₂)_(n)— or (N-1-3C alkyl)pyridinonyl-CH₂—;

hetAr¹ is a 6-membered heteroaryl having 1-2 ring N atoms and optionallysubstituted with one or more substituents independently selected from(1-6C)alkyl, (1-4C)alkoxy, halogen, CF₃, or (3-6C)cycloalkyl;

m is 0, 1 or 2;

hetAr² is a 5-membered heteroaryl ring having 2-3 ring heteroatomsindependently selected from N and S where at least one of saidheteroatoms is N, wherein said ring is optionally substituted with oneor more substituents independently selected from (1-6C)alkyl;

hetAr³ is a bicyclic 5,6-fused heteroaryl ring having two ring nitrogenatoms;

hetCyc¹ is a 6-membered saturated heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O and optionallysubstituted with —C(═O)(1-6C alkyl) or —C(═O)O(1-6C alkyl);

Ar¹ is phenyl optionally substituted with one or more substituentsindependently selected from halogen, (1-6C)alkyl, CN, CF₃, OH,(1-6C)alkoxy, —C(═O)OH, —C(═O)O(1-6C alkyl), —C(═O)NR^(a)R^(b) orbenzyloxy;

R^(a) and R^(b) are independently H or (1-6C)alkyl;

n is 0, 1 or 2;

R² is H, F, Cl or CH₃;

R³ is H, F or Cl;

R⁴ is H, CN, F, Cl, Br, —OMe, —OCF₃, —CF₃, —CH(OH)CH₂OH or —C(═O)NH₂;

R⁵ is selected from:

H,

halogen,

CN,

OH,

hetAr⁴,

hetAr⁵,

hetCyc²,

hetCyc³(1-4Calkyl)-,

hetCyc⁴(1-4C)alkoxy,

hetCyc⁵(1-4C)alkoxy,

(1-3C alkoxy)(1-4C)alkoxy,

hydroxy(1-6C)alkoxy,

dihydroxy(2-6C)alkoxy,

(1-6C)alkoxy,

[hydroxy(2-4C)alkyl)amino]-(1-4C)alkyl,

[(1-4C alkoxy)(1-4C alkyl)amino](1-4C)alkyl,

[di(1-4C alkyl)amino](1-4C)alkyl,

(1-4C alkyl)C(═O)—,

hydroxy(1-6C)alkyl,

dihydroxy(2-6C)alkyl,

[di(1-3C alkyl)amino](1-4C)alkoxy,

N-(1-3C alkyl)pyridinone,

hetAr⁶,

hetCyc⁶C(═O)—,

(hetCyc⁷)-O—,

hetCyc⁸(1-4C)alkoxy,

difluoroamino(1-4C)alkoxy,

[(1-4C alkoxy)carbonylamide]difluoro(1-4C)alkoxy,

(1-4C alkyl)C(═O)NH(2-4C)alkylthio-,

(1-4Calkyl)OC(═O)—, and

R^(c)R^(d)NC(═O)—;

hetAr⁴ is a 5-membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S, wherein said ring is optionallysubstituted with one or more substituents independently selected from(1-6C)alkyl and [di(1-3C alkyl)amino]CH₂—;

hetAr⁵ is a 6-membered heteroaryl ring having 1-2 ring N atoms andoptionally substituted with one or more substituents independentlyselected from (1-6C)alkyl;

hetAr⁶ is a 9-membered partially unsaturated bicyclic heterocyclic ringhaving 3 ring N atoms and optionally substituted with one or moresubstituents independently selected from (1-6C)alkyl;

hetCyc² is a 5-7 membered saturated or partially unsaturatedheterocyclic ring having 1-2 ring heteroatoms selected from N and O,wherein said ring is optionally substituted with one or moresubstituents independently selected from (1-6C)alkyl,hydroxy(1-6C)alkyl, OH and oxo, provided said oxo is on a carbon atom;

hetCyc³ is a 4-6 membered heterocyclic ring having 1-2 ring N atoms andoptionally substituted with one or more substituents independentlyselected from (1-6C)alkyl, (1-6C)alkoxy and halogen;

hetCyc⁴ is a 4-7 membered heterocycle having 1-2 ring heteroatomsindependently selected from N, O and S, wherein one of said ringnitrogen atoms is optionally oxidized to N(O) and wherein said S ringatom is optionally oxidized to SO or SO₂, wherein hetCyc⁴ is optionallysubstituted with one or more substituents independently selected fromhalogen, OH, (1-6C)alkyl, (1-4C alkoxy)(1-6C)alkyl, (1-4C)alkyl-OC(═O)—and (1-6C)alkoxy;

hetCyc⁵ is a spiro heterocycle having 2 ring heteroatoms independentlyselected from N and O, wherein hetCyc⁵ is optionally substituted with agroup selected from (1-6C)alkyl;

hetCyc⁶ is a 6 membered heterocyclic ring having 1-2 ring N atoms andoptionally substituted with one or more substituents independentlyselected from (1-6C)alkyl;

hetCyc⁷ is a 4-6 membered heterocyclic ring having one or two ring Natoms and optionally substituted with one or more substituentsindependently selected from (1-6C)alkyl and OH;

hetCyc⁸ is a bridged 8-membered heterocyclic ring having 2 ring atomsselected from N and O wherein at least one of said heteroatoms is N,wherein said ring is optionally substituted with (1-6C)alkyl;

R^(c) is H or (1-4C)alkyl;

R^(d) is (1-4C)alkyl, hetCyc¹⁰-, amino(1-4C)alkyl, or [di(1-4Calkyl)amino](1-4C) alkyl;

hetCyc¹⁰ is a 5 membered heterocycle having a ring N atom and optionallysubstituted with one or more substituents independently selected from(1-6C)alkyl; and

R⁶ is H or Cl.

Compounds of Formula I are inhibitors of type III receptor tyrosinekinases such as PDGFR, cFMS and cKIT, and are useful for treatingdiseases and disorders selected from fibrosis, bone-related diseases,cancer, autoimmune disorders, inflammatory diseases, cardiovasculardiseases and pain in a mammal in need thereof.

In one embodiment, R¹ is hetAr¹(CH₂)_(m)—, hetAr²CH₂— or hetAr³CH₂—.

In one embodiment, R¹ is hetAr¹(CH₂)_(m)—, wherein hetAr¹ is a6-membered heteroaryl having 1-2 ring N atoms and optionally substitutedwith one or more substituents independently selected from (1-6C)alkyl,(1-4C)alkoxy, halogen, CF₃, or (3-6C)cycloalkyl.

In one embodiment, hetAr¹ is pyridyl or pyrimidyl. In one embodiment,hetAr¹ is pyridyl.

Examples of (1-6C)alkyl substituents for hetAr include (1-4C)alkylsubstituents such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl and tert-butyl.

Particular examples of (1-4C)alkoxy substituents for hetAr¹ includemethoxy and ethoxy.

A particular example of a halogen substituent for hetAr¹ is fluoro.

Particular examples of (3-6C)cycloalkyl substituents for hetAr¹ includecyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In certain embodiments, R¹ is hetAr¹(CH₂)_(m)—, where hetAr¹ is a 6membered heteroaryl ring having 1-2 ring nitrogen atoms and optionallysubstituted with one or more substituents independently selected frommethyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl,methoxy, ethoxy, fluoro, CF₃, cyclopropyl, cyclobutyl, or cyclopentyl.In certain embodiments, hetAr¹ is optionally substituted with one or twoof said substituents. In certain embodiments, hetAr¹ is pyridyloptionally substituted with one or more substituents independentlyselected from methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl,tert-butyl, methoxy, ethoxy, fluoro, CF₃, cyclopropyl, cyclobutyl, orcyclopentyl. In certain embodiments, m is 0. In certain embodiments, mis 1. In certain embodiments, m is 2.

Particular values for R¹ when represented by hetAr¹(CH₂)_(m)— includethe structures:

In one embodiment, R¹ is hetAr²CH₂—, where hetAr² is a 5-memberedheteroaryl ring having 2-3 ring heteroatoms independently selected fromN and S where at least one of said heteroatoms is N, wherein said ringis optionally substituted with one or more substituents independentlyselected from (1-6C)alkyl. In one embodiment, hetAr² is a 5-memberedheteroaryl ring having 2 ring heteroatoms independently selected from Nand S where at least one of said heteroatoms is N, wherein said ring isoptionally substituted with one or more substituents independentlyselected from (1-6C)alkyl. Particular examples of hetAr² rings includethiazolyl, pyrazolyl, and imidazolyl. Examples of (1-6C)alkylsubstituents for hetAr² include (1-4C)alkyl groups, for example methyl,ethyl, propyl and isopropyl. In one embodiment, hetAr² is optionallysubstituted with one or two of said substituents.

Particular examples of R¹ when represented by hetAr²CH₂ include thestructures:

In one embodiment, R¹ is hetAr³CH₂—, where hetAr³ is a bicyclic5,6-fused heteroaryl ring having two ring nitrogen atoms. A particularexample of hetAr³CH₂— is a group having the structure:

In one embodiment, R¹ is (3-6C cycloalkyl)-CH₂—. Particular exampleincludes cyclopropylmethyl and cyclohexylmethyl having the structures:respectively.

In one embodiment, R¹ is (3-6C cycloalkyl)-CH₂—, hetCyc¹CH₂—,Ar¹(CH₂)_(n)— or (N-1-3C alkyl)pyridinonyl-CH₂—.

In one embodiment, R¹ is hetCyc¹CH₂—, where hetCyc¹ is a 6-memberedsaturated heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N and O and optionally substituted with —C(═O)(1-6C alkyl)or —C(═O)O(1-6C alkyl). Examples of hetCyc¹ include tetrahydropyranyl,piperidinyl and morpholinyl rings. In one embodiment, hetCyc¹ isoptionally substituted with —C(═O)CH₃ or —C(═O)OC(CH₃)₃.

Particular examples of R¹ when represented by hetCyc¹CH₂— include thestructures:

In one embodiment, R¹ is Ar¹(CH₂)_(n)—, where Ar¹ is phenyl optionallysubstituted with one or more substituents independently selected fromhalogen, (1-6C)alkyl, CN, CF₃, OH, (1-6C)alkoxy, —C(═O)OH, —C(═O)O(1-6Calkyl), —C(═O)NR^(a)R^(b) or benzyloxy.

In one embodiment, R¹ is Ar¹(CH₂)_(n)—, where Ar¹ is phenyl optionallysubstituted with one or more substituents independently selected from F,Cl, methyl, CN, CF₃, OH, methoxy, —C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂,—C(═O)NHCH₃, —C(═O)N(CH₃)₂ or benzyloxy.

In one embodiment, n is 0. In one embodiment, n is 1. In one embodiment,n is 2.

Particular examples of R¹ when represented by Ar¹(CH₂)_(n)— include thestructures:

In one embodiment, R¹ is N-(1-3C alkyl)pyridinonyl-CH₂—, that is, apyridinonyl-CH₂— substituent wherein the nitrogen ring atom of thepyridinonyl is substituted with (1-3C)alkyl. A particular example of R¹is the structure:

In one embodiment, R⁵ is H.

In one embodiment, R⁵ is halogen. In one embodiment, R⁵ is F or Br.

In one embodiment, R⁵ is CN.

In one embodiment, R⁵ is OH.

In one embodiment, R⁵ is hetAr⁴, where hetAr⁴ is a 5-membered heteroarylring having 1-3 ring heteroatoms independently selected from N, O and S,wherein said ring is optionally substituted with one or moresubstituents independently selected from (1-6C)alkyl and [di(1-3Calkyl)amino]CH₂—. In one embodiment, at least one of said ringheteroatoms is nitrogen. In embodiments wherein at least one of saidring heteroatoms is nitrogen, hetAr⁴ can be a nitrogen radical (that is,hetAr⁴ is linked to the imidazopyridine ring of Formula I through a ringnitrogen atom of hetAr⁴) or a carbon radical (that is, hetAr⁴ is linkedto the imidazopyridine ring of Formula I through a ring carbon atom ofhetAr⁴). Examples of hetAr⁴ include pyrazolyl, triazolyl, thiadiazolyl,oxadiazolyl and furanyl rings optionally substituted with one or moresubstituents independently selected from (1-6C)alkyl and [di(1-3Calkyl)amino]CH₂—. In certain embodiments hetAr⁴ is optionallysubstituted with one or two of said substituents. In certain embodimentshetAr⁴ is optionally substituted with one or two substituentsindependently selected from methyl and Me₂NCH₂—. Particular examples ofR⁵ when represented by hetAr⁴ include the structures:

In one embodiment, R⁵ is hetAr⁴ where hetAr⁴ is a 5-membered heteroarylring having 2 ring nitrogen atoms, wherein said ring is optionallysubstituted with one or more substituents independently selected from(1-6C)alkyl, for example one or more substituents independently selectedfrom (1-4C)alkyl, such as methyl. In one embodiment, hetAr⁴ is selectedfrom:

In one embodiment, R⁵ is hetAr⁵, where hetAr⁵ is a 6-membered heteroarylring having 1-2 ring N atoms and optionally substituted with one or moresubstituents independently selected from (1-6C)alkyl. Examples of hetAr⁵include pyrimidyl and pyridyl rings optionally substituted with asubstituent selected from (1-6C alkyl), for example one or moresubstituents independently selected from (1-4C)alkyl, for example methylor ethyl. Particular examples of R⁵ when represented by hetAr⁵ includethe structures:

In one embodiment, R⁵ is hetAr⁵, where hetAr⁵ is pyridyl optionallysubstituted with one or more substituents independently selected from(1-6C)alkyl, for example one or more substituents independently selectedfrom (1-4C)alkyl, such as methyl or ethyl. In one embodiment, hetAr⁵ ispyridyl optionally substituted with methyl. In one embodiment, hetAr⁵is:

In one embodiment, R⁵ is hetCyc², where hetCyc² is a 5-7 memberedsaturated or partially unsaturated heterocyclic ring having 1-2 ringheteroatoms selected from N and O, wherein said ring is optionallysubstituted with one or more substituents independently selected from(1-6C)alkyl, hydroxy(1-4C)alkyl, OH and oxo, provided said oxo is on acarbon atom. In one embodiment, at least one of said ring heteroatoms ofhetCyc² is N. In one embodiment when hetCyc² includes at least one Nring atom, hetCyc² is a nitrogen radical, that is, hetCyc² is linked tothe imidazopyridine ring of Formula I through a ring nitrogen atom ofhetCyc². In one embodiment when hetCyc² includes at least one N ringatom, hetCyc² is a carbon radical, that is, hetCyc² is linked to theimidazopyridine ring of Formula I through a ring carbon atom of hetCyc².Examples of hetCyc² include pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, tetrahydropyridinyl and diazepanyl rings optionallysubstituted with one or more substituents independently selected from(1-6C)alkyl, hydroxy(1-4C)alkyl, OH and oxo. In certain embodiments,hetCyc² is substituted with one or more substituents independentlyselected from methyl, ethyl, OH, HOCH₂CH₂— and oxo. In one embodiment,hetCyc² is optionally substituted with one or two of said substituents.

In one embodiment, examples of R⁵ when represented by hetCyc² includethe structures:

In one embodiment, R⁵ is hetCyc², where hetCyc² is a 5-6 memberedsaturated or partially unsaturated heterocycle having 1-2 ring nitrogenatoms. In one embodiment, hetCyc² is selected from the structures:

In one embodiment, R⁵ is hetCyc³(1-4Calkyl)-, where hetCyc³ is a 4-6membered heterocyclic ring having 1-2 ring N atoms and optionallysubstituted with one or more substituents independently selected from(1-6C)alkyl, (1-6C)alkoxy and halogen. Examples of hetCyc³ includeazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl ringsoptionally substituted with one or more substituents independentlyselected from (1-6C)alkyl, (1-6C)alkoxy and halogen. In one embodiment,hetCyc³ is optionally substituted with one or more substituentsindependently selected from (1-4C)alkyl, (1-6C)alkoxy and halogen. Incertain embodiments hetCyc³ is substituted with one or more substituentsindependently selected from methyl, ethyl, fluoro and methoxy. Incertain embodiments, hetCyc³ is substituted with one or two of saidsubstituents. In certain embodiments, R⁵ is hetCyc³(1-3C)alkyl.Particular examples of R⁵ when represented by hetCyc³(1-4Calkyl)-include the structures:

In one embodiment, R⁵ is hetCyc³(1-4Calkyl)- where hetCyc³ is a 5-6membered heterocyclic ring having 1-2 ring heteroatoms independentlyselected from N and O, wherein hetCyc³ is optionally substituted with asubstituent selected from (1-6C)alkyl. In one embodiment,hetCyc³(1-4Calkyl)- is selected from the structures:

In one embodiment, R⁵ is hetCyc⁴(1-4C)alkoxy, that is, a (1-4C)alkoxygroup as defined herein wherein one of the carbon atoms is substitutedwith hetCyc⁴, where hetCyc⁴ is a 4-7 membered heterocycle having 1-2ring heteroatoms independently selected from N, O and S, wherein one ofsaid ring nitrogen atoms is optionally oxidized to N(O) and wherein saidS ring atom is optionally oxidized to SO or SO₂, wherein hetCyc⁴ isoptionally substituted with one or more substituents independentlyselected from halogen, OH, (1-6C)alkyl, (1-4C alkoxy)(1-6C)alkyl,(1-4C)alkyl-OC(═O)— and (1-6C)alkoxy. Examples of hetCyc⁴ includeazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,diazepanyl, 1-methyl-piperazinyl-1-oxide, andthiomorpholinyl-1,1-dioxide, each of which is optionally substitutedwith one or more one or more substituents independently selected fromhalogen, OH, (1-6C)alkyl, (1-4C alkoxy)(1-6C)alkyl, (1-4C)alkyl-OC(═O)—and (1-6C)alkoxy. In certain embodiments, hetCyc⁴ is optionallysubstituted with one or more substituents independently selected formmethyl, ethyl, isopropyl, fluoro, methoxy, CH₂OCH₂CH₂—, OH and(CH₃)₃COC(═O)—. In certain embodiments hetCyc⁴ is optionally substitutedwith one to three of said substituents. In certain embodiments, R⁵ ishetCyc⁴(1-2C)alkoxy.

In one embodiment, examples of R⁵ when represented byhetCyc⁴(1-4C)alkoxy include the structures:

In one embodiment, R⁵ is hetCyc⁴(1-4C)alkoxy, that is, a (1-4C)alkoxygroup as defined herein wherein one of the carbon atoms is substitutedwith hetCyc⁴, where hetCyc⁴ is a 5-6 membered heterocycle having 1-2ring heteroatoms independently selected form N and O, wherein said ringis optionally substituted with one or more substituents independentlyselected from (1-6C)alkyl, (1-4C alkoxy)(1-6C)alkyl and(1-4C)alkyl-OC(═O)—. In one embodiment, hetCyc⁴ is optionallysubstituted with one to three substituents independently selected frommethyl, ethyl, isopropyl, CH₃OCH₂CH₂— and (CH₃)₃COC(═O)—. In oneembodiment, examples of R⁵ when represented by hetCyc⁴(1-4C)alkoxyinclude the structures:

In one embodiment, R⁵ is hetCyc⁵(1-4C)alkoxy, that is, a (1-4C)alkoxygroup as defined herein wherein one of the carbon atoms is substitutedwith hetCyc⁵, where hetCyc⁵ is a spiro heterocycle having 2 ringheteroatoms independently selected from N and O and is optionallysubstituted with a substituent selected from (1-6C)alkyl. As usedherein, the term “spiro heterocycle” refers to a system comprising tworings, one of which being a nitrogen containing heterocycle, said ringshaving one carbon atom in common, such as, for instance, a2-oxa-6-azaspiro[3.3]heptane or a 2,6-diazaspiro[3.3]heptane ring systemhaving the structure:

respectively. In one embodiment, hetCyc⁵ is optionally substituted witha group selected from (1-6C)alkyl, for example methyl.

In one embodiment, examples of R⁵ when represented byhetCyc⁵(1-4C)alkoxy include the structures:

In one embodiment, R⁵ is (1-3C alkoxy)(1-4C)alkoxy, that is, a(1-4C)alkoxy group as defined herein wherein one of the carbon atoms issubstituted with a (1-3C alkoxy) substituent such as methoxy. Aparticular example of R⁵ when represented by (1-3C alkoxy)(1-4C)alkoxyincludes a methoxyethoxy substituent having the structure:

In one embodiment, R⁵ is hydroxy(1-6C)alkoxy, that is, a (1-6C)alkoxygroup wherein one of the carbon atoms is substituted with hydroxy. Inone embodiment, R⁵ is hydroxy(1-4C)alkoxy. A particular example of R⁵when represented by hydroxy(1-6C)alkoxy includes the structure:

In one embodiment, R⁵ is dihydroxy(2-6C)alkoxy, that is, a (2-6C)alkoxygroup wherein two of the carbon atoms are each substituted with ahydroxy group. In one embodiment, R⁵ is dihydroxy(2-4C)alkoxy. Aparticular example of R⁵ when represented by dihydroxy(2-6C)alkoxy isthe structure:

In one embodiment, R⁵ is (1-6C)alkoxy. In one embodiment, R⁵ is(1-4C)alkoxy. In one embodiment, R⁵ is methoxy or ethoxy.

In one embodiment, R⁵ is [hydroxy(2-4C)alkyl)amino](1-4C)alkyl, that is,a (1-4C)alkyl group wherein one of the carbon atoms is substituted witha [hydroxy(2-4C alkyl)]amino substituent, for example a HOCH₂CH₂NH—substituent. A particular example of R⁵ is the structure:

In one embodiment, R⁵ is [(1-4C alkoxy)(1-4C alkyl)amino](1-4C)alkyl,that is, a (1-4C)alkyl group wherein one of the carbon atoms issubstituted with a [(1-4C alkoxy)(1-4C alkyl)amino substituent, forexample a methoxy(1-4C alkyl)NH— substituent. A particular example of R⁵when represented by [(1-4C alkoxy)(1-4C alkyl)]amino(1-4C)alkyl is thestructure:

In one embodiment, R⁵ is [di(1-4C alkyl)amino](1-4C)alkyl, that is, a(1-4C)alkyl group wherein one of the carbon atoms is substituted with adi(1-4C alkyl)amino. In one embodiment, R⁵ is dimethylamino(1-4C alkyl).Particular examples when R⁵ is [di(1-4C alkyl)amino](1-4C)alkyl includethe structures:

In one embodiment, R⁵ is (1-4C alkyl)C(═O)—. A particular example of R⁵includes the structure:

In one embodiment, R⁵ is hydroxy(1-6C)alkyl, that is, a (1-6C)alkylgroup as defined herein wherein one of the carbon atoms is substitutedwith hydroxy. In one embodiment, R⁵ is hydroxy(1-4C)alkyl. Particularexamples of R⁵ include the structures:

In one embodiment, R⁵ is dihydroxy(2-6C)alkyl, that is, a (1-6C)alkylgroup as defined herein wherein two of the carbon atoms are eachsubstituted with a hydroxy group. In one embodiment, R⁵ isdihydroxy(2-4C)alkyl. A particular example of R⁵ is the structure:

In one embodiment, R⁵ is [di(1-3C alkyl)amino](1-4C)alkoxy, that is, a(1-4C)alkoxy group wherein one of the carbon atoms is substituted with adi(1-3C alkyl)amino, for example a dimethylamino group. A particularexample of R⁵ when represented by [di(1-3C alkyl)amino](1-4C)alkoxyincludes the structure:

In one embodiment, R⁵ is N-(1-3C alkyl)pyridinone. A particular exampleincludes N-methylpyridinone which can be represented by the structure:

In one embodiment, R⁵ is hetAr⁶, where hetAr⁶ is a 9-membered partiallyunsaturated bicyclic heterocyclic ring having 3 ring N atoms andoptionally substituted with one or more substituents independentlyselected from (1-6C)alkyl. Examples of hetAr⁶ include a 5 memberedheteroaryl ring fused to a 6-membered saturated heterocyclic ring,wherein one or both of said rings are optionally substituted with agroup independently selected from (1-6C alkyl). Particular examplesinclude 5,6,7,8-tetrahydroimidazopyrazine rings optionally substitutedwith a substituent selected from (1-6C alkyl), for example one or moresubstituents independently selected from (1-4C)alkyl, for example methylor ethyl. Particular values for R⁵ when represented by hetAr⁶ includethe structures:

In one embodiment, R⁵ is hetCyc⁶C(═O)—, where hetCyc⁶ is a 6 memberedheterocyclic ring having 1-2 ring N atoms and optionally substitutedwith one or more substituents independently selected from (1-6C)alkyl.Examples of hetCyc⁶ include piperidinyl and piperazinyl rings optionallysubstituted with one or more substituents independently selected from(1-6C)alkyl, for example (1-4C)alkyl, such as methyl or ethyl.Particular examples of R⁵ when represented by hetCyc⁶C(═O)— include thestructures:

In one embodiment, R⁵ is (hetCyc⁷)-O—, where hetCyc⁷ is a 4-6 memberedheterocyclic ring having one or two ring N atoms and optionallysubstituted with one or more substituents independently selected from(1-6C)alkyl and OH. Examples of hetCyc⁷ include azetidinyl,pyrrolidinyl, piperidinyl and piperazinyl rings optionally substitutedwith one or more substituents independently selected from (1-6C)alkyland OH. In certain embodiments hetCyc⁷ is azetidinyl, pyrrolidinyl orpiperidinyl optionally substituted with one or more substituentsindependently selected from methyl and OH. In certain embodimentshetCyc⁷ is substituted with one or two of said substituents. Particularexamples of R⁵ when represented by (hetCyc⁷)-O— include the structures:

In one embodiment, R⁵ is hetCyc⁸(1-4C)alkoxy, that is, a (1-4C)alkoxygroup as defined herein wherein one of the carbon atoms is substitutedwith hetCyc⁸, where hetCyc⁸ is a bridged 8-membered heterocyclic ringhaving 2 ring atoms selected from N and O wherein at least one of saidheteroatoms is N, wherein said ring is optionally substituted with(1-6C)alkyl. Examples of hetCyc⁸ rings include3,8-diazabicyclo[3.2.1]octane and 8-oxa-3-azabicyclo[3.2.1]octane ringsoptionally substituted with (1-6C)alkyl. Particular examples of R⁵ whenrepresented by hetCyc⁸(1-4C)alkoxy include the structures:

In one embodiment, R⁵ is difluoroamino(1-4C)alkoxy, that is, a(1-4C)alkoxy group as defined herein wherein one of the hydrogen atomsof the alkoxy portion as defined herein is replaced with an amino groupand two of the hydrogen atoms of the alkoxy portion as defined hereinare each replaced with a fluorine atom. A particular example of R⁵ whenrepresented by difluoroamino(1-4C)alkoxy is the structure:

In one embodiment, R⁵ is [(1-4Calkoxy)carbonylamide]difluoro(1-4C)alkoxy, that is, a (1-4C)alkoxy groupas defined herein wherein two of the carbon atoms are each substitutedwith a fluorine atom and one of the carbon atoms is substituted with a(1-4C alkoxy)carbonylamide, for example a (CH₃)₃OC(═O)NH— group. Aparticular example of R⁵ when represented by [(1-4Calkoxy)carbonylamide]difluoro(1-4C)alkoxy is the structure:

In one embodiment, R⁵ is (1-4C alkyl)C(═O)NH(2-4C)alkylthio-, that is, a(2-4C)alkylthio group in which the radical is on the sulfur atom,wherein one of the carbon atoms is substituted with a (1-4Calkyl)C(═O)NH— substituent. A particular example of R⁵ when representedby (1-4C alkyl)C(═O)NH(2-4C)alkylthio includes the structure:

In one embodiment, R⁵ is (1-4Calkyl)OC(═O)—. A particular example of R⁵is the structure:

In one embodiment, R⁵ is R^(c)R^(d)NC(═O)—, where Re is H or methyl andR^(d) is (1-4C)alkyl, hetCyc¹⁰-, amino(1-4C)alkyl or [di(1-4Calkyl)amino](1-4C alkyl). In one embodiment, R⁶ is H. In one embodiment,Re is methyl.

In one embodiment, R⁵ is R^(c)R^(d)NC(═O)—, where R^(c) is H or methyland R^(d) is hetCyc¹⁰. Examples of hetCyc¹⁰ groups include pyrrolidinylrings optionally substituted with (1-6C)alkyl, for example (1-4C)alkyl,such as methyl or ethyl. Particular examples of R⁵ include thestructures:

In one embodiment, R⁵ is R^(c)R^(d)NC(═O)—, where Re is H or methyl andR^(d) is amino(1-4C)alkyl. A particular example of R⁵ is the structure:

In one embodiment, R⁵ is R^(c)R^(d)NC(═O)—, where Re is H or methyl andR^(d) is [di(1-4C alkyl)amino](1-4C)alkyl-. In one embodiment R^(d) isdimethylamino(1-4C alkyl). A particular example of R⁵ includes thestructure:

In one embodiment, R⁵ is R^(c)R^(d)NC(═O)—, where Re is H or methyl andR^(d) is (1-4C)alkyl. A particular example of R⁵ includes thestructures:

In one embodiment, R⁵ is selected from H, halogen, CN, OH, hetAr⁴,hetAr⁵, hetCyc², hetCyc³(1-4Calkyl)-, hetCyc⁴(1-4C)alkoxy,hetCyc⁵(1-4C)alkoxy, (1-3C alkoxy)(1-4C)alkoxy, hydroxy(1-6C)alkoxy,dihydroxy(2-6C)alkoxy, (1-4C)alkoxy,[hydroxy(2-4C)alkyl)amino]-(1-4C)alkyl, [(1-4C alkoxy)(1-4Calkyl)amino](1-4C)alkyl, [di(1-4C alkyl)amino](1-4C)alkyl, (1-4Calkyl)C(═O)—, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, [di(1-3Calkyl)amino](1-4C)alkoxy and N-(1-3C alkyl)pyridinone.

In certain embodiments, R⁵ is selected from H, halogen, CN and OH.

In certain embodiments, R⁵ is selected from hetAr⁴, hetAr⁵, hetCyc² andhetCyc³(1-4Calkyl)-.

In certain embodiments, R⁵ is selected from hetAr⁴ or hetAr⁵.

In certain embodiments, R⁵ is selected from hetCyc⁴(1-4C)alkoxy,hetCyc⁵(1-4C)alkoxy, (1-3C alkoxy)(1-4C)alkoxy, hydroxy(1-6C)alkoxy,dihydroxy(2-6C)alkoxy, (1-4C)alkoxy and 3C alkyl)amino](1-4C)alkoxy.

In certain embodiments, R⁵ is selected from hetCyc² orhetCyc³(1-4Calkyl)-.

In certain embodiments, R⁵ is hetCyc⁴(1-4C)alkoxy orhetCyc⁵(1-4C)alkoxy.

In certain embodiments, R⁵ is hetCyc⁴(1-4C)alkoxy.

In certain embodiments, R⁵ is (1-3C alkoxy)(1-4C)alkoxy.

In certain embodiments, R⁵ is selected from (1-3C alkoxy)(1-4C)alkoxy,hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, (1-6C)alkoxy,[hydroxy(2-4C)alkyl)amino]-(1-4C)alkyl, [(1-4C alkoxy)(1-4Calkyl)amino](1-4C)alkyl, [di(1-4C alkyl)amino](1-4C)alkyl, (1-4Calkyl)C(═O)—, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl and [di(1-3Calkyl)amino](1-4C)alkoxy.

In certain embodiments, R⁵ is selected from[hydroxy(2-4C)alkyl)amino]-(1-4C)alkyl, [(1-4C alkoxy)(1-4Calkyl)amino](1-4C)alkyl, [di(1-4C alkyl)amino](1-4C)alkyl,hydroxy(1-4C)alkyl and dihydroxy(2-4C)alkyl.

In certain embodiments, R⁵ is selected from hetAr⁶, hetCyc⁶C(═O)—,(hetCyc⁷)-O—, hetCyc⁸(1-4C)alkoxy, difluoroamino(1-4C)alkoxy, [(1-4Calkoxy)carbonylamide]difluoro(1-4C)alkoxy, (1-4Calkyl)C(═O)NH(2-4C)alkylthio-, (1-4Calkyl)OC(═O)—, andR^(c)R^(d)NC(═O)—.

In certain embodiments of Formula I, R² is H.

In certain embodiments of Formula I, R² is CH₃.

In certain embodiments of Formula I, R² is F.

In certain embodiments of Formula I, R² is Cl.

In certain embodiments of Formula I, R² is H or CH₃.

In certain embodiments of Formula I, R³ is H.

In certain embodiments of Formula I, R³ is F.

In certain embodiments of Formula I, R³ is Cl.

In certain embodiments of Formula I, R⁴ is H.

In certain embodiments of Formula I, R⁴ is CN.

In certain embodiments of Formula I, R⁴ is F.

In certain embodiments of Formula I, R⁴ is Cl.

In certain embodiments of Formula I, R⁴ is Br.

In certain embodiments of Formula I, R⁴ is —OMe.

In certain embodiments of Formula I, R⁴ is —OCF₃.

In certain embodiments of Formula I, R⁴ is —CF₃.

In certain embodiments of Formula I, R⁴ is —CH(OH)CH₂OH.

In certain embodiments of Formula I, R⁴ is —C(═O)NH₂.

In certain embodiments of Formula I, R⁴ is selected from H, CN, Br,—OMe, —CH(OH)CH₂OH or —C(═O)NH₂.

In certain embodiments of Formula I, R⁶ is H.

In certain embodiments of Formula I, R⁶ is Cl.

In certain embodiments of Formula I, R³, R⁴, R⁵ and R⁶ are H.

In one embodiment of Formula I, R¹ is hetAr¹(CH₂)_(m)—, hetAr²CH₂—,hetAr³CH₂—, (3-6C cycloalkyl)-CH₂—, hetCyc¹CH₂—, Ar¹(CH₂)_(n)— or(N-1-3C alkyl)pyridinonyl-CH₂—; R² is H, F, Cl or CH₃; R³ is H, F or Cl;R⁴ is H, CN, Br, —OMe, —CH(OH)CH₂OH or —C(═O)NH₂; R⁵ is selected from H,halogen, CN, OH, hetAr⁴, hetAr⁵, hetCyc², hetCyc³(1-4Calkyl)-,hetCyc⁴(1-4C)alkoxy, hetCyc⁵(1-4C)alkoxy, (1-3C alkoxy)(1-4C)alkoxy,hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, (1-6C)alkoxy,[hydroxy(2-4C)alkyl)amino]-(1-4C)alkyl, [(1-4C alkoxy)(1-4Calkyl)amino](1-4C)alkyl, [di(1-4C alkyl)amino](1-4C)alkyl, (1-4Calkyl)C(═O)—, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, [di(1-3Calkyl)amino](1-4C)alkoxy, and N-(1-3C alkyl)pyridinone; and R⁶ is H orCl; where m, hetAr¹, hetAr², hetAr³, hetCyc¹, Ar¹, n, hetAr⁴, hetAr⁵,hetCyc², hetCyc³, hetCyc⁴ and hetCyc⁵ are as defined for Formula I.

In one embodiment of Formula I, R¹ is hetAr¹(CH₂)_(m)—, hetAr²CH₂— orhetAr³CH₂—; R² is F, Cl, H or CH₃; R³ is H; R⁴ is H; R⁵ is selected fromH, halogen, CN, OH, hetAr⁴, hetAr⁵, hetCyc², hetCyc³(1-4Calkyl)-,hetCyc⁴(1-4C)alkoxy, hetCyc⁵(1-4C)alkoxy, (1-3C alkoxy)(1-4C)alkoxy,hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, (1-6C)alkoxy,[hydroxy(2-4C)alkyl)amino]-(1-4C)alkyl, [(1-4C alkoxy)(1-4Calkyl)amino](1-4C)alkyl, [di(1-4C alkyl)amino](1-4C)alkyl, (1-4Calkyl)C(═O)—, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, [di(1-3Calkyl)amino](1-4C)alkoxy, and N-(1-3C alkyl)pyridinone; and R⁶ is H;where m, hetAr¹, hetAr², hetAr³, hetAr⁴, hetAr⁵, hetCyc², hetCyc³,hetCyc⁴ and hetCyc⁵ are as defined for Formula I.

In one embodiment of Formula I, R¹ is hetAr¹(CH₂)_(m)—; R² is F, Cl, Hor CH₃; R³ is H; R⁴ is H; R⁵ is selected from H, halogen, CN, OH,hetAr⁴, hetAr⁵, hetCyc², hetCyc³(1-4Calkyl)-, hetCyc⁴(1-4C)alkoxy,hetCyc⁵(1-4C)alkoxy, (1-3C alkoxy)(1-4C)alkoxy, hydroxy(1-6C)alkoxy,dihydroxy(2-6C)alkoxy, (1-6C)alkoxy,[hydroxy(2-4C)alkyl)amino]-(1-4C)alkyl, [(1-4C alkoxy)(1-4Calkyl)amino](1-4C)alkyl, [di(1-4C alkyl)amino](1-4C)alkyl, (1-4Calkyl)C(═O)—, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, [di(1-3Calkyl)amino](1-4C)alkoxy, and N-(1-3C alkyl)pyridinone; and R⁶ is H;where m, hetAr¹, hetAr⁴, hetAr⁵, hetCyc², hetCyc³, hetCyc⁴ and hetCyc⁵are as defined for Formula I.

In one embodiment of Formula I, R¹ is hetAr¹(CH₂)_(m)—, hetAr²CH₂— orhetAr³CH₂—; R² is F, Cl, H or CH₃; R³ is H; R⁴ is H; R¹ ishetCyc⁴(1-4C)alkoxy or hetCyc⁵(1-4C)alkoxy; and R⁶ is H; where m,hetAr¹, hetAr², hetAr³, hetCyc⁴ and hetCyc⁵ are as defined for FormulaI.

In one embodiment of Formula I, R¹ is hetAr¹ (CH₂)_(m)—, hetAr²CH₂— orhetAr³CH₂; R² is CH₃; R³ is H; R⁴ is H; R⁵ is hetCyc⁴(1-4C)alkoxy orhetCyc⁵(1-4C)alkoxy; and R⁶ is H; where m, hetAr¹, hetAr², hetAr³,hetCyc⁴ and hetCyc⁵ are as defined for Formula I.

In one embodiment of Formula I, R¹ is hetAr¹(CH₂)_(m)—, hetAr²CH₂— orhetAr³CH₂; R² is F, Cl, H or CH₃; R³ is H; R⁴ is H; R⁵ is hetAr⁴ orhetAr⁵; and R⁶ is H; where m, hetAr¹, hetAr², hetAr³, hetAr⁴ and hetAr⁵are as defined for Formula I.

In one embodiment of Formula I, R¹ is hetAr¹(CH₂)_(m)—, hetAr²CH₂— orhetAr³CH₂; R² is F, Cl, H or CH₃; R³ is H; R⁴ is H; R⁵ is hetCyc² orhetCyc³(1-4Calkyl)-; and R⁶ is H; where m, hetAr¹, hetAr², hetAr³,hetCyc² and hetCyc³ are as defined for Formula I.

In one embodiment of Formula I, R¹ is (3-6C cycloalkyl)-CH₂—,hetCyc¹CH₂—, Ar¹(CH₂)_(n)— or (N-1-3C alkyl)pyridinonyl-CH₂—; R² is F,Cl, H or CH₃; R³ is H; R⁴ is H; R⁵ is selected from H, halogen, CN, OH,hetAr⁴, hetAr⁵, hetCyc², hetCyc³(1-4Calkyl)-, hetCyc⁴(1-4C)alkoxy,hetCyc⁵(1-4C)alkoxy, (1-3C alkoxy)(1-4C)alkoxy, hydroxy(1-6C)alkoxy,dihydroxy(2-6C)alkoxy, (1-6C)alkoxy,[hydroxy(2-4C)alkyl)amino]-(1-4C)alkyl, [(1-4C alkoxy)(1-4Calkyl)amino](1-4C)alkyl, [di(1-4C alkyl)amino](1-4C)alkyl, (1-4Calkyl)C(═O)—, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, [di(1-3Calkyl)amino](1-4C)alkoxy, and N-(1-3C alkyl)pyridinone; and R⁶ is H;where hetCyc¹, Ar¹, n, hetAr⁴, hetAr⁵, hetCyc², hetCyc³, hetCyc⁴ andhetCyc⁵ are as defined for Formula I.

In one embodiment, Formula I does not include the following compounds:3-((4-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)benzoicacid and7-(2-methoxyethoxy)-N-(1-(piperidin-4-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide.

The terms “(1-6C)alkyl”, “(1-4C)alkyl” “(2-4C)alkyl” and “(2-6C)alkyl”as used herein refers to saturated linear or branched-chain monovalenthydrocarbon radicals of one to six carbon atoms, one to four carbonatoms, two to four carbon atoms, or two to six carbon atoms,respectively. Examples include, but are not limited to, methyl, ethyl,1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl,2-methyl-2-propyl, pentyl and hexyl.

The terms “(1-6C)alkoxy”, “(1-4C)alkoxy”, “(2-4C)alkoxy” and“(2-6C)alkoxy” as used herein refer to saturated linear orbranched-chain monovalent alkoxy radicals of one to six carbon atoms,one to four carbon atoms, two to four carbon atoms, or two to six carbonatoms, respectively, wherein the radical is on the oxygen atom. Examplesinclude methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

When a chemical formula is used to describe a substituent, the dash onthe left or the right side of the formula indicates that the freevalance is on the left of the right portion, respectively, of thesubstituent.

The term “halogen” includes fluoro, chloro, bromo and iodo.

It will be appreciated that certain compounds according to the inventionmay contain one or more centers of asymmetry and may therefore beprepared and isolated as a mixture of isomers such as a racemic ordiastereomeric mixture, or in an enantiomerically or diastereomericallypure form. It is intended that all stereoisomeric forms of the compoundsof the invention, including but not limited to, diastereomers,enantiomers and atropisomers, as well as mixtures thereof such asracemic mixtures, form part of the present invention.

It may be advantageous to separate reaction products from one anotherand/or from starting materials. The desired products of each step orseries of steps is separated and/or purified (hereinafter separated) tothe desired degree of homogeneity by techniques common in the art.Typically such separations involve multiphase extraction,crystallization from a solvent or solvent mixture, distillation,sublimation, or chromatography. Chromatography can involve any number ofmethods including, for example: reverse-phase and normal phase; sizeexclusion; ion exchange; high, medium and low pressure liquidchromatography methods and apparatus; small scale analytical; simulatedmoving bed (“SMB”) and preparative thin or thick layer chromatography,as well as techniques of small scale thin layer and flashchromatography. One skilled in the art will apply techniques most likelyto achieve the desired separation.

Enantiomers can be separated by converting the enantiomeric mixture intoa diastereomeric mixture by reaction with an appropriate opticallyactive compound (e.g., chiral auxiliary, such as a chiral alcohol orMosher's acid chloride), separating the diastereomers and converting(e.g., hydrolyzing) the individual diastereoisomers to the correspondingpure enantiomers. Enantiomers can also be separated by use of a chiralHPLC column. Diastereomeric mixtures can be separated into theirindividual diastereomers on the basis of their physical chemicaldifferences by methods well known to those skilled in the art, such asby chromatography and/or fractional crystallization.

A single stereoisomer, for example, an enantiomer, substantially free ofits stereoisomer may be obtained by resolution of the racemic mixtureusing methods known in the art, such as (1) formation of ionic,diastereomeric salts with chiral compounds and separation by fractionalcrystallization or other methods, (2) formation of diastereomericcompounds with chiral derivatizing reagents, separation of thediastereomers, and conversion to the pure stereoisomers, and (3)separation of the substantially pure or enriched stereoisomers directlyunder chiral conditions. See: Wainer, Irving W., ed. DrugStereochemistry: Analytical Methods and Pharmacology. New York: MarcelDekker, Inc., 1993.

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts may be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid, can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(Eliel, E., and S. Wilen. Stereochemistry of Organic Compounds. NewYork: John Wiley & Sons, Inc., 1994, p. 322). Diastereomeric compoundscan be formed by reacting asymmetric compounds with enantiomericallypure chiral derivatizing reagents, such as menthyl derivatives, followedby separation of the diastereomers and hydrolysis to yield the pure orenriched enantiomer. A method of determining optical purity involvesmaking chiral esters, such as a menthyl ester, e.g., (−) menthylchloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III, Peyton.“Resolution of (±)-5-Bromonornicotine. Synthesis of (R)- and(S)-Nomicotine of High Enantiomeric Purity.” J. Org. Chem. Vol. 47, No.21 (1982): pp. 4165-4167), of the racemic mixture, and analyzing the ¹HNMR spectrum for the presence of the two atropisomeric enantiomers ordiastereomers. Stable diastereomers of atropisomeric compounds can beseparated and isolated by normal- and reverse-phase chromatographyfollowing methods for separation of atropisomeric naphthyl-isoquinolines(WO 96/15111).

By method (3), a racemic mixture of two enantiomers can be separated bychromatography using a chiral stationary phase (Lough, W. J., ed. ChiralLiquid Chromatography. New York: Chapman and Hall, 1989; Okamoto,Yoshio, et al. “Optical resolution of dihydropyridine enantiomers byhigh-performance liquid chromatography using phenylcarbamates ofpolysaccharides as a chiral stationary phase.” J. of Chromatogr. Vol.513 (1990): pp. 375-378). Enriched or purified enantiomers can bedistinguished by methods used to distinguish other chiral molecules withasymmetric carbon atoms, such as optical rotation and circulardichroism.

In one embodiment, a compound of Formula I can be enriched in oneenantiomer over the other by up to 80% enantiomeric excess. In oneembodiment, a compound of Formula I can be enriched in one enantiomerover the other by up to 85% enantiomeric excess. In one embodiment, acompound of Formula I can be enriched in one enantiomer over the otherby up to 90% enantiomeric excess. In one embodiment, a compound ofFormula I can be enriched in one enantiomer over the other by up to 95%enantiomeric excess.

As used herein, the term “enantiomeric excess” means the absolutedifference between the mole fraction of each enantiomer.

It will further be appreciated that an enantiomer of a compound of theinvention can be prepared by starting with the appropriate chiralstarting material.

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds of the invention. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined.

It will also be appreciated that certain compounds of Formula I may beused as intermediates for the preparation of further compounds ofFormula I.

The compounds of Formula I include salts thereof. In certainembodiments, the salts are pharmaceutically acceptable salts. Inaddition, the compounds of Formula I include other salts of suchcompounds which are not necessarily pharmaceutically acceptable salts,and which may be useful as intermediates for preparing and/or purifyingcompounds of Formula I and/or for separating enantiomers of compounds ofFormula I.

It will further be appreciated that the compounds of Formula I and theirsalts may be isolated in the form of solvates, and accordingly that anysuch solvate is included within the scope of the present invention.

Compounds of the invention may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. That is, an atom, in particular when mentioned in relation toa compound according to Formula I, comprises all isotopes and isotopicmixtures of that atom, either naturally occurring or syntheticallyproduced, either with natural abundance or in an isotopically enrichedform. For example, when hydrogen is mentioned, it is understood to referto ¹H, ²H, ³H or mixtures thereof; when carbon is mentioned, it isunderstood to refer to 1C, ¹²C, ¹³C ¹⁴C or mixtures thereof; whennitrogen is mentioned, it is understood to refer to ¹³N, ¹⁴N ¹⁵N ormixtures thereof; when oxygen is mentioned, it is understood to refer to¹⁴O, ¹⁵O, ¹⁶O, ¹⁷O, ¹⁸O or mixtures thereof, and when fluoro ismentioned, it is understood to refer to ¹⁸F, ¹⁹F or mixtures thereof.The compounds according to the invention therefore also comprisecompounds with one or more isotopes of one or more atom, and mixturesthereof, including radioactive compounds, wherein one or morenon-radioactive atoms has been replaced by one of its radioactiveenriched isotopes. Radiolabeled compounds are useful as therapeuticagents, e.g., cancer therapeutic agents, research reagents, e.g., assayreagents, and diagnostic agents, e.g., in vivo imaging agents. Allisotopic variations of the compounds of the present invention, whetherradioactive or not, are intended to be encompassed within the scope ofthe present invention.

The present invention further provides a process for the preparation ofa compound of Formula I or a salt thereof as defined herein whichcomprises:

(a) coupling a corresponding compound of formula II

where Z¹ is COOH or a reactive derivative thereof with a correspondingcompound of formula III

in the presence of a coupling reagent; or

(b) coupling a corresponding compound of formula IV

with a compound of formula III

in the presence of a base; or

(c) for a compound of Formula I where R⁵ is hetCyc⁴(1-4C)alkoxy,(hetCyc⁷)-O—, hetCyc⁸(1-4C)alkoxy, hydroxy(1-6C)alkoxy,difluoroamino(1-4C)alkoxy, or [(1-4Calkoxy)carbonylamide]difluoro(1-4C)alkoxy, reacting a correspondingcompound of formula V

where X¹ is F or Cl, with a compound having the formula R^(5a)—O— whereR^(5a) is hetCyc⁴(1-4C)alkyl-OH, hetCyc⁷-OH, hetCyc⁸(1-4C)alkyl-OH,P¹O-(1-6C)alkyl-OH, difluoroamino(1-4C)alkyl-OH or [(1-4Calkoxy)carbonylamide]difluoro(1-4C)alkyl-OH, respectively, in thepresence of a base, where P¹ is a hydroxyl protecting group; or

(d) for a compound of Formula I where R⁵ is hetCyc² where hetCyc² is anitrogen radical, reacting a corresponding compound of formula V-a

with a compound having the formula hetCyc²-H; or

(e) for a compound of Formula I where R⁵ is hetAr⁴ wherein hetAr⁴ is anitrogen radical, reacting a corresponding compound of formula V-a

with a compound having the formula hetAr⁴—H in the presence of a base;or

(f) for a compound of Formula I where R⁵ is a carbon linked substituentselected from hetAr⁴, hetAr⁵, and N-(1-3C alkyl)pyridinone, reacting acorresponding compound of formula V-b

with a compound having the formula VI

where Ring E is a carbon-linked radical selected from hetAr⁴, hetAr⁵,and N-(1-3C alkyl)pyridinonyl, respectively, in the presence of apalladium catalyst and a base; or

(g) for a compound of Formula I where R⁵ is hetAr⁴ or hetAr⁶ wherehetAr⁴ and hetAr⁶ are carbon radicals, reacting a corresponding compoundof formula V-b

with a compound having the formula hetAr⁴—H or hetAr⁶—H, respectively,in the presence of a palladium catalyst and a base and optionally in thepresence of a ligand; or

(h) for a compound of Formula I where R⁵ is hetCyc⁶C(═O)—, reacting acorresponding compound having the formula VII

with a compound having the formula hetCyc⁶-H in the presence of acoupling reagent; or

(i) for a compound of Formula I where R⁵ has the structure:

reacting a corresponding compound having the formula VIII

where R^(5b) is

respectively, with formaldehyde in the presence of a reducing agent; or

(j) for a compound of Formula I where R⁵ is R^(c)R^(d)NC(═O)—, reactinga corresponding compound of formula IX

with a compound having the formula R^(c)R^(d)NH in the presence of acoupling agent; or

(k) for a compound of Formula I wherein R⁵ is an oxadiazole substituenthaving the formula:

where R^(g) is H or Me, cyclizing a corresponding compound having theformula X

in the presence of trimethoxymethane or triethoxyethane, respectively;or

(1) for a compound of Formula I wherein R⁵ is 1,3,4-thiadiazol-2-yl,cyclizing a corresponding compound having the formula XI

in the presence of P₂S₅; or

(m) for a compound of Formula I wherein R⁵ is hetCyc³(1-2Calkyl)- wherehetCyc³ is a nitrogen radical, [(1-4C alkoxy)(1-4Calkyl)]amino(1-2C)alkyl, or [hydroxy(2-4C)alkyl)]amino-(1-2C)alkyl,reacting a corresponding compound of formula XII

where n is 0 or 1 and Z is H or Me, with hetCyc³-H, [(1-4C alkoxy)(1-4Calkyl)]NH₂ or [hydroxy(2-4C)alkyl)]NH₂, respectively, in the presence ofa reducing agent; or

(n) for a compound of Formula I wherein R¹ is hetAr²CH₂— and hetAr² is apyrazolyl ring having a ring N atom substituted with a substituentselected from or (1-6C)alkyl-, reacting a corresponding compound havingthe formula XIII

with a compound having the formula (1-6C)alkyl-X², respectively, whereinX² is a leaving group or atom, in the presence of a base; or

(o) for a compound of Formula I wherein R¹ is N-(1-3Calkyl)pyridinonyl-CH₂—, coupling a corresponding compound having theformula XIV

with (1-3C alkyl)-L¹ where L¹ is a leaving group or atom in the presenceof a base; or

(p) for a compound of Formula I wherein R⁵ is hetCyc³CH₂— where hetCyc³is a nitrogen radical, coupling a corresponding compound having theformula XV

where L² is a leaving group with a compound having the formula hetCyc³-Hin the presence of a base; or

(q) for a compound of Formula I where R⁵ is hetCyc⁴(1-4C)alkoxy andhetCyc⁴ is N-methylpiperazine-1-oxide, reacting a corresponding compoundof formula XVI

where n is 0, 1, 2 or 3, with an oxidizing agent; or

(r) for a compound of Formula I wherein R⁵ is hetCyc³(1-4Calkyl)- wherehetCyc³ is a nitrogen radical, reacting a corresponding compound havingthe formula XVII

where n is 0, 1, 2 or 3, and L³ is a leaving group, with a correspondingcompound having the formula hetCyc³ in the presence of a base; or

(s) for compound of Formula I where R⁵ is (1-4Calkyl)C(═O)NH(2-4C)alkylthio-, coupling a corresponding compound havingthe formula V

where X¹ is F or Cl, with a compound having the formula (1-4Calkyl)C(═O)NH(2-4C)alkyl-SH in the presence of a base; or

(t) for a compound of Formula I wherein R⁵ is CH₃C(═O)—, coupling acorresponding compound having the formula V-b

with a compound having the formula

in the presence of a palladium catalyst and a ligand, followed bytreatment with acid; or

(u) for a compound of Formula I wherein R⁵ is HO(CH₂CH₂)—, treating acorresponding compound having the formula XVIII

with a reducing agent; and

removing any protecting groups if desired and forming a salt thereof ifdesired.

Referring to method (a), the coupling of the compound of formula II witha compound of formula III may be performed using conventional amide bondformation conditions, for example by treating the carboxylic acid withan activating agent, followed by addition of the amine in the presenceof a base. Suitable activating agents include oxalyl chloride, thionylchloride, EDCI, HATU, and HOBt. Suitable bases include amine bases, forexample triethylamine, diisopropylethylamine, pyridine, or excessammonia. Suitable solvents include DCM, DCE, THF, and DMF.

Alternatively, the amide bond formation can be performed by coupling areactive derivative of a carboxylic acid of formula II, for example anacid halide such as an acid chloride, or a lithium salt thereof.

Referring to method (b), suitable bases include alkali metal hydridessuch as NaH, alkali metal amine bases such as lithium diisopropylamideand silicon-containing alkali metal amides (e.g., sodiumhexamethyldisilazide or lithium hexamethyldisilazide).

Referring to method (c), suitable bases include alkali metal carbonatesor alkoxides, such as for example cesium carbonate or sodiumtert-butoxide.

Referring to method (d), suitable solvents include toluene and THF. Thereaction is conveniently performed at elevated temperatures for exampleat temperatures between 110-120° C.

Referring to method (e), suitable bases include alkali metal hydrides,such as sodium hydride or potassium hydride. Convenient solvents includeaprotic solvents such as ethers (for example tetrahydrofuran orp-dioxane), DMF, or acetone. The reaction can be conveniently performedat elevated temperatures, for example temperatures ranging from 90 to110° C.

Referring to method (f), suitable palladium catalysts include Pd₂(dba)₃,Pd(PPh₃)₄, and Pd(OAc)₂. Convenient solvents include aprotic solventssuch as ethers (for example tetrahydrofuran or p-dioxane), toluene orDMF. The reaction can be conveniently performed at elevatedtemperatures, for example temperatures ranging from 70 to 90° C.

Referring to method (g), suitable palladium catalysts include Pd₂(dba)₃,Pd(PPh₃)₄, and Pd(OAc)₂. Suitable ligands include trifuran-2-ylphophine,rac-BINAP, DIPHOS and the like. The base may be, for example, an alkalimetal carbonate or alkoxide, such as for example cesium carbonate orsodium tert-butoxide. Convenient solvents include aprotic solvents suchas ethers (for example tetrahydrofuran or p-dioxane), toluene or DMF.

Referring to method (h), suitable coupling reagents include1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), DCC,1,1′-carbonyldiimidazole (CDI) and the like.

Referring to method (i), suitable reducing agents include Na(OAc)₃BH andNaCNBH₃. Suitable solvents include neutral solvents such asacetonitrile, THF, and dichloroethane.

Referring to method (j), examples of suitable coupling agents includeCDI, EDCI, phosgene, and bis(trichloromethyl) carbonate. Suitablesolvents include dichloromethane, dichloroethane, THF, and DMF. Thereaction is conveniently performed at ambient temperature or at elevatedtemperatures, e.g., at about 60-80° C.

Referring to method (k), the reaction is conveniently performed withexcess trimethoxymethane or triethoxyethane at elevated temperatures,for example at 100-120° C.

Referring to method (1), suitable solvents include aprotic solvents suchas ethers (for example tetrahydrofuran or p-dioxane), toluene and/orDMF. The reaction is conveniently performed at elevated temperatures,for example at 100-120° C.

Referring to methods (m) and (u), suitable reducing agents includeNa(OAc)₃BH and NaCNBH₃. Suitable solvents include methanol, ethanol, anddichloromethane or mixtures thereof. The reaction is convenientlyperformed at ambient temperature.

Referring to method (n), the leaving group X² may be an alkylsulfonyl orarylsulfonyl group, for example, a triflate group, or an arylsulfonyloxygroup or an alkylsulfonyloxy group, such as a mesylate or a tosylategroup. Alternatively, X² may be a leaving atom such as Cl or Br. Thebase may be, for example, an alkali metal carbonate, hydroxide oralkoxide, such as for example cesium carbonate, sodium carbonate,potassium carbonate, sodium hydroxide, cesium hydroxide or potassiumtert-butoxide. Convenient solvents include aprotic solvents such asethers (for example tetrahydrofuran or p-dioxane), toluene, DMF or DME.The reaction can be conveniently performed at ambient temperature.

Referring to method (o), the base may be, for example, an alkali metalhydride or carbonate, such as sodium hydride, potassium hydride, sodiumcarbonate, potassium carbonate or cesium carbonate. Convenient solventsinclude aprotic solvents such as ethers (for example tetrahydrofuran orp-dioxane), DMF, or acetone.

Referring to method (p), the leaving group L² may be an alkylsulfonyloxygroup, such as a tosylate or a mesylate group. The base may be an alkalimetal carbonate or bicarbonate, such as sodium or potassium carbonate orbicarbonate. Convenient solvents include aprotic solvents such as ethers(for example tetrahydrofuran or p-dioxane) and DMF. The reaction can beconveniently performed at a temperature ranging from ambient temperatureto 50° C.

Referring to method (q), suitable oxidizing agents include organicperbenzoic acids such as metachloroperbenzoic acid. Convenient solventsinclude aprotic solvents such as DCM, ethers (for exampletetrahydrofuran or p-dioxane) and DMF. The reaction temperature for thisoxidizing step is typically in the range from −25° C. to ambienttemperature, for example between −20° C. and 0° C.

Referring to method (r), the leaving group L³ may be an alkylsulfonyloxygroup, such as a tosylate or a mesylate group. Convenient solventsinclude aprotic solvents such as ethers (for example tetrahydrofuran orp-dioxane) and DMF.

Referring to method (s), suitable bases include an alkali metalcarbonate or alkoxide, such as for example cesium carbonate or sodiumtert-butoxide. Convenient solvents include aprotic solvents such asethers (for example tetrahydrofuran or p-dioxane) and DMF.

Referring to method (t), suitable palladium catalysts include Pd(PPh₃)₄,Pd₂(dba)₃, Pd(OAc)₂, Pd(PPh₃)₂Cl₂ and1,1′-bis(diphenylphosphino)ferrocene-PdCl₂-dichloromethane complex.

Compounds of the Formulas V, V-a, V-b, VII, VIII, IX, X, XI, XII, XIII,XIV, XV, XVI, XVII, and XVIII are also believed to be novel and areprovided as further aspects of the invention.

Amine groups in compounds described in any of the above methods may beprotected with any convenient amine protecting group, for example asdescribed in Greene & Wuts, eds., “Protecting Groups in OrganicSynthesis”, John Wiley & Sons, Inc. Examples of amine protecting groupsinclude acyl and alkoxycarbonyl groups, such as t-butoxycarbonyl (BOC),and [2-(trimethylsilyl)ethoxy]methyl (SEM). Likewise, carboxyl groupsmay be protected with any convenient carboxyl protecting group, forexample as described in Greene & Wuts, eds., “Protecting Groups inOrganic Synthesis”, John Wiley & Sons, Inc. Examples of carboxylprotecting groups include (1-6C)alkyl groups, such as methyl, ethyl andt-butyl. Alcohol groups may be protected with any convenient alcoholprotecting group, for example as described in Greene & Wuts, eds.,“Protecting Groups in Organic Synthesis”, John Wiley & Sons, Inc.Examples of alcohol protecting groups include benzyl, trityl, silylethers, and the like.

The compounds of Formula I represent novel potent inhibitors of proteintyrosine kinases, such as PDGFR, cFMS and/or cKIT and may be useful inthe prevention and treatment of disorders resulting from actions ofthese kinases.

The ability of compounds of the invention to act as inhibitors of PDGFRmay be demonstrated by the assays described in Examples A and/or B.

The ability of compounds of the invention to act as inhibitors of cFMSmay be demonstrated by the assay described in Example C.

The ability of compounds of the invention to act as inhibitors of cKITmay be demonstrated by the assay described in Example D.

Compounds of Formula I may be of therapeutic value in the treatment ofdiseases or disorders selected from fibrosis, bone-related diseases,cancer, autoimmune disorders, inflammatory diseases, cardiovasculardiseases, pain and burns. In one embodiment, compounds of Formula I maybe of therapeutic value in the treatment of diseases or disordersselected from fibrosis, bone-related diseases, cancer, autoimmunedisorders, inflammatory diseases, cardiovascular diseases and pain.

In one embodiment, the compounds of Formula I are useful for thetreatment of fibrotic diseases. Examples of fibrosis include idiopathicpulmonary fibrosis (IPF), nephrogenic systemic fibrosis (NSF), cirrhosisof the liver, diabetic-induced nephropathy, cardiac fibrosis (forexample, endomyocardial fibrosis), mediastinal fibrosis, myelofibrosis,retroperitoneal fibrosis, Crohn's disease, keloid formation, sclerodermaand systemic sclerosis. Additional examples of fibrotic diseases includefocal segmental glomerular sclerosis (FSGS), interstitial lung diseasein systemic sclerosis (SSc-ILD), primary biliary cirrhosis, ethanolcirrhosis, interstitial fibrosis and tubular atrophy (CAD),proliferative vitreoretinopathy, and scarring (hypertrophic and keloid),

In one embodiment, the compounds of Formula I are useful for thetreatment of bone-related diseases.

Examples of bone-related diseases include metastatic bone disease,treatment-induced bone loss, osteoporosis, rheumatoid arthritis,ankylosing spondylitis, Paget's disease, and periodontal disease. Theosteoporosis may be attributed to (1) menopause in women, (2) aging inmen or women, (3) suboptimal bone growth during childhood andadolescence that resulted in failure to reach peak bone mass, and/or (4)bone loss secondary to other disease conditions, eating disorders,medications and/or medical treatments (for example, as a result oftreatment with glucocorticoids, aromatase inhibition therapy, oranti-androgen therapy).

Other osteolytic diseases that can be treated according to the presentinvention are more localized. A particular example is metastatictumor-induced osteolysis. In this condition, bone cancers or bonemetastases induce localized osteolysis that causes pain, bone weaknessand fractures. Such localized osteolysis also permits tumors to growlarger by creating more space for them in the bone and releasing growthfactors from the bone matrix. Cancers presently known to causetumor-induced osteolysis include hematological malignancies (e.g.,myeloma and lymphoma) and solid tumors (e.g., breast, prostate, lung,renal and thyroid), all of which the present invention contemplatestreating.

In one embodiment, the compounds of Formula I are useful for thetreatment of cancers and proliferative disorders. Examples includemultiple myeloma, acute myeloid leukemia (AML), chronic myeloid leukemia(CML), prostate cancer, breast cancer, ovarian cancer, melanoma,glioblastoma multiforme, giant cell tumor of bone (also known asosteoclastome), giant cell tumor of the tendon sheath (also known astenosynovial giant cell tumor or TGCT), metastasis of tumors to othertissues, other chronic myeloproliferative diseases such asmyelofibrosis, and pigmented villonodular synovitis (PVNS).

In one embodiment, the compounds of Formula I are useful for thetreatment of autoimmune disorders and inflammatory diseases.

Examples of autoimmune disorders and inflammatory diseases include butare not limited to, rheumatoid arthritis, osteoarthritis, psoriaticarthritis, ankylosing spondylitis, Adult Still's, glomerulonephritis,osteoporosis, Sjogren's syndrome, inflammatory bowel disease, ulcerativecolitis, Crohn's disease, Langerhans cell histiocytosis, hemophagocyticsyndrome, multicentric reticulohistiocytosis, and Paget's disease.Additional examples of autoimmune diseases and disorders include primarysclerosing cholangitis and transplant rejection (including hepatic,renal and heart/lung transplants).

In one embodiment, the compounds of Formula I are useful for thetreatment of cardiovascular diseases. Examples of cardiovasculardiseases include atherosclerosis, peripheral vascular disease, coronaryartery disease, ischemia/reperfusion, hypertension, restenosis,pulmonary arterial hypertension and arterial inflammation. Additionalexamples of cardiovascular diseases include acute respiratory distresssyndrome (ARDA), arteriovenous (AV) fistula patency and veno-occlusivedisease (post-HSC/BMT).

In one embodiment, the compounds of Formula I are useful for thetreatment of pain. In one embodiment, the compounds of Formula I areuseful for the treatment of pain as a result of nerve injury. In oneembodiment, the compounds of Formula I are useful for the treatment ofneuropathic pain associated with nerve inflammation (neuritis) in theabsence of nerve injury. Such pain syndromes include back pain,temporomandibular joint (TMJ) disorder, and rheumatoid arthritis.

In one embodiment, the compounds of Formula I are useful for thetreatment of burns.

Compounds of Formula I may be administered alone as a sole therapy orcan be administered in addition with one or more other substances and/ortreatments that work by the same or a different mechanism of action.Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate administration of the individual components ofthe treatment.

Accordingly, the invention further provides methods of treatingbone-related diseases in mammals, including humans, by administration toa mammal in need thereof a therapeutically effective amount of at leastone compound of Formula I or a pharmaceutically acceptable salt thereof.The compounds may be administered alone or may be administered incombination with one or more drugs for the treatment of bone-relateddiseases that work by the same or a different mechanism of action.

The invention further provides methods of treating cancer in mammals,including humans, by administration to a mammal in need thereof atherapeutically effective amount of at least one compound of Formula Ior a pharmaceutically acceptable salt thereof.

In the field of medical oncology it is normal practice to use acombination of different forms of treatment to treat each patient withcancer. In medical oncology the other component(s) of such conjointtreatment in addition to compositions of the present invention may be,for example, surgery, radiotherapy, chemotherapy, signal transductioninhibitors and/or monoclonal antibodies.

Accordingly, the compounds of Formula I may be administered incombination with one or more agents selected from mitotic inhibitors,alkylating agents, anti-metabolites, antisense DNA or RNA, intercalatingantibiotics, growth factor inhibitors, signal transduction inhibitors,cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators,proteasome inhibitors, topoisomerase inhibitors, biological responsemodifiers, anti-hormones, angiogenesis inhibitors, cytostatic agentsanti-androgens, targeted antibodies, HMG-CoA reductase inhibitors, andprenyl-protein transferase inhibitors.

The invention also provides methods of treating cardiovascular diseasesin mammals, including humans, by administration to a mammal in needthereof at least one compound of Formula I or a pharmaceuticallyacceptable salt thereof. The compounds may be administered alone or maybe administered in combination with one or more drugs for the treatmentof cardiovascular diseases that work by the same or a differentmechanism of action.

The invention also provides methods of treating inflammatory diseases inmammals, including humans, by administration of at least one compound ofFormula I or a pharmaceutically acceptable salt thereof. The compoundsmay be administered alone for the treatment of inflammatory disease ormay be administered in combination with one or more drugs for treatinginflammatory diseases that work by the same or a different mechanism ofaction, such as gold salts or methotrexate.

The invention also provides methods of treating pain in mammals,including humans, by administration to a mammal in need thereof at leastone compound of Formula I or a pharmaceutically acceptable salt thereof.The compounds may be administered alone for the treatment of pain or maybe administered in combination with one or more drugs for treating painthat work by the same or a different mechanism of action.

The invention also provides methods of treating burns in mammals,including humans, by administration to a mammal in need thereof at leastone compound of Formula I or a pharmaceutically acceptable salt thereof.

As used herein, the terms “treatment” or “treating” mean an alleviation,in whole or in part, of symptoms associated with a disorder or condition(e.g., bone-related diseases, fibrosis, cancer, autoimmune disorders,inflammatory diseases, cardiovascular diseases or pain as describedherein), or slowing, or halting of further progression or worsening ofthose symptoms.

In one embodiment, compounds of Formula I are useful for preventing adisease or disorder selected from fibrosis, bone-related diseases,cancer, autoimmune disorders, inflammatory diseases, cardiovasculardiseases and pain in a mammal.

As used herein, the term “preventing” means the prevention of the onset,recurrence or spread, in whole or in part, of the disease or condition(e.g., bone-related diseases, fibrosis, cancer, autoimmune disorders,inflammatory diseases, cardiovascular diseases or pain as describedherein), or a symptom thereof.

As used herein, the phrase “effective amount” means an amount ofcompound that, when administered to a mammal in need of such treatment,is sufficient to (i) treat or prevent a particular disease, condition,or disorder, (ii) attenuate, ameliorate, or eliminate one or moresymptoms of the particular disease, condition, or disorder, or (iii)prevent or delay the onset of one or more symptoms of the particulardisease, condition, or disorder described herein.

The amount of a compound of Formula I that will correspond to such anamount will vary depending upon factors such as the particular compound,disease condition and its severity, the identity (e.g., weight) of themammal in need of treatment, but can nevertheless be routinelydetermined by one skilled in the art.

As used herein, the term “mammal” refers to a warm-blooded animal thathas or is at risk of developing a disease described herein and includes,but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters,and primates, including humans.

Compounds of the invention may be administered by any convenient route,e.g. into the gastrointestinal tract (e.g. rectally or orally), thenose, lungs, musculature or vasculature, or transdermally or dermally.Compounds may be administered in any convenient administrative form,e.g. tablets, powders, capsules, solutions, dispersions, suspensions,syrups, sprays, suppositories, gels, emulsions, patches etc. Suchcompositions may contain components conventional in pharmaceuticalpreparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulkingagents, and further active agents. If parenteral administration isdesired, the compositions will be sterile and in a solution orsuspension form suitable for injection or infusion. Such compositionsform a further aspect of the invention.

The present invention further provides a pharmaceutical composition,which comprises a compound of Formula I or a pharmaceutically acceptablesalt thereof, as defined hereinabove. In one embodiment, thepharmaceutical composition includes the compound of Formula I togetherwith a pharmaceutically acceptable diluent or carrier.

The present invention further provides a compound of Formula I or apharmaceutically acceptable salt thereof, for use in therapy. In oneembodiment, the invention provides a compound of Formula I or apharmaceutically acceptable salt thereof, for use in the treatment of adisease or disorder selected from fibrosis, bone-related diseases,cancer, autoimmune disorders, inflammatory diseases, cardiovasculardiseases and pain in a mammal. In one embodiment, the disease isfibrosis. In one embodiment, the disease is a bone-related disease. Inone embodiment, the disease is cancer. In one embodiment, the disease isan autoimmune disorder. In one embodiment, the disease is aninflammatory disease. In one embodiment, the disease is cardiovasculardisease. In one embodiment, the disorder is pain. In one embodiment, thedisorder is burns.

According to a further aspect, the present invention provides the use ofa compound of Formula I or a pharmaceutically acceptable salt thereof,in the treatment of a disease or disorder selected from fibrosis,bone-related diseases, cancer, autoimmune disorders, inflammatorydiseases, cardiovascular diseases and pain in a mammal. In oneembodiment, the disease is fibrosis. In one embodiment, the disease is abone-related disease. In one embodiment, the disease is cancer. In oneembodiment, the disease is an autoimmune disorder. In one embodiment,the disease is an inflammatory disease. In one embodiment, the diseaseis cardiovascular disease. In one embodiment, the disorder is pain. Inone embodiment, the disorder is burns.

According to a further aspect, the present invention provides the use ofa compound of Formula I in the manufacture of a medicament for thetreatment of a disease or disorder selected from fibrosis, bone-relateddiseases, cancer, autoimmune disorders, inflammatory diseases,cardiovascular diseases and pain in a mammal, which comprisesadministering to said mammal a therapeutically effective amount of acompound of Formula I or a pharmaceutically acceptable salt thereof. Inone embodiment, the disease is fibrosis. In one embodiment, the diseaseis a bone-related disease. In one embodiment, the disease is cancer. Inone embodiment, the disease is an autoimmune disorder. In oneembodiment, the disease is an inflammatory disease. In one embodiment,the disease is cardiovascular disease. In one embodiment, the disorderis pain. In one embodiment, the disorder is burns.

EXAMPLES

The following examples illustrate the invention. In the examplesdescribed below, unless otherwise indicated all temperatures are setforth in degrees Celsius. Reagents were purchased from commercialsuppliers such as Aldrich Chemical Company, Lancaster, Alfa, Aesar, TCI,Maybridge, or other suitable suppliers, and were used without furtherpurification unless otherwise indicated. Tetrahydrofuran (THF),dichloromethane (DCM, methylene chloride), toluene, dimethylformamide(DMF) and dioxane were purchased from DriSolve or other commercialvendors and used as received.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsby syringe. Glassware was oven dried and/or heat dried or dried under astream of dry nitrogen.

Column chromatography was done on a Biotage system (Manufacturer: DyaxCorporation) having a silica gel or C-18 reverse phase column, or on asilica SepPak cartridge (Waters), or using conventional flash columnchromatography on silica gel.

Abbreviations used herein have the following meanings:

APCI Atmospheric Pressure Chemical Ionization BOC tert-butoxycarbonylDCE 1,2-Dichloroethane DCM Dichloromethane DMA N,N-Dimethylacetamide DMFN,N-Dimethylformamide DMSO dimethylsulfoxide DPPF1,1′-bis(diphenylphosphino)ferrocene EDCI1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide GF/F Glass Fiber FilterHATU (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl- uroniumhexafluorophosphate) HOBt Hydroxybenzotriazole IPA Isopropyl alcohol LAHLithium Aluminum Hydride LHMDS Lithium bis(trimethylsilyl)amide (alsoknown as lithium hexamethyldisilazide) MTBE tert-butyl-methylether NMPN-Methylpyrrolidone P₂S₅ Phosphorus pentasulfide Pd(PPh₃)₄Tetrakis(triphenylphosphine)palladium(0) PdCl₂(dppf)*dcm1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)- dichloridedichloromethane complex TEA triethylamine TFA Trifluoroacctic acid THFTetrahydrofuran X-PHOSdicyclohexyl[2′,4′,6′-tris(1-methylethyl)[1,1′-biphenyl]-2-yl]-phosphine

Example A Phospho PDGFR Cell Assay

Compounds were screened for inhibition of PDGFR beta phosphorylation inthe HS27 human fibroblast cell line. Cells were seeded into a 96 welltissue culture plate, then incubated overnight in a 37° C., 5% CO₂incubator. The following day, cells were treated for one hour with testcompound dilutions. After stimulation with PDGF-BB ligand for 5 minutes,cells were lysed and added to a sandwich ELISA plate from R&D Systems todetect levels of phospho PDGFR beta. A standard 4-parameter logisticmodel was fit to the inhibitor dose response curves, with the IC₅₀ beingdefined as the concentration of inhibitor giving 50 percent of control(POC).

Example B Phospho PDGFR LICOR Cell Assay

Compounds were screened for inhibition of PDGFR beta phosphorylation inthe HS27 human fibroblast cell line. Cells were seeded into a 96 welltissue culture plate, then incubated overnight in a 37° C./5% CO₂incubator. The following day, cells were treated for one hour with testcompound dilutions. After stimulation with PDGF-BB ligand for 10minutes, cells were washed with PBS and fixed in 3.7% formaldehyde inPBS for 10 minutes. This was followed by washing in PBS/0.2% TritonX-100 and permeabilizing in 100% MeOH for 10 minutes. Cells wereincubated in blocking buffer for 1 hour. Antibodies to phosphorylatedPDGFRβ and total ERK were added to the cells and incubated for 3 hours.After washing with PBS/0.2% Triton X-100, the cells were incubated withfluorescently-labeled secondary antibodies for an additional hour. Cellswere then washed with PBS and analyzed for fluorescence at bothwavelengths using the Odyssey Infrared Imaging System (LI-CORBiosciences). Phosphorylated PDGFR signal was normalized to total ERKsignal. A standard 4-parameter logistic model was fit to the inhibitordose response curves, with the IC₅₀ being defined as the concentrationof inhibitor giving 50 percent of control (POC).

Example C cFMS Cell-Based Assay

The ability of compounds of Formula I to inhibit cFMS activation incells was determined by the following assay. THP-1 cells (human acutemonocytic leukemia cell line) were serum-starved for 4 hours prior totreatment with compounds of Formula I for 1 hour. The concentration ofcompounds of Formula I was varied over a 9-point, 3-fold dilution serieswith 5,000 nM typically being the highest dose. Cell culture andtreatment were carried out in a humidified 37° C., 5% CO₂ incubator.Treated cells were stimulated with 250 ng/mL recombinant human MCSF for1 minute to induce activation of cFMS. Cells were lysed in a mannerwhich preserves phosphoproteins, and the lysate was analyzed by ELISA(R&D Systems, Human Phospho-M-CSF R DuoSet IC DYC3268), in which totalcFMS protein in the lysate is captured and phosphotyrosine residues ofcFMS are detected. A standard curve, made using purified phospho-M-CSF Rprotein, was used to quantify phospho-c-FMS in compound-treated wells. Astandard 4-parameter logistic model was fit to the inhibitor doseresponse curves, with the IC₅₀ being defined as the concentration ofinhibitor giving 50 percent of control (POC).

Example D c-KIT Cell-Based Assay

The ability of compounds of Formula I to inhibit c-KIT activation incells was determined by the following assay. M-07e cells (human acutemegakaryoblastic leukemia cell line) were serum-starved for 4 hoursprior to treatment with compounds of Formula I for 1 hour. Theconcentration of compounds of Formula I was varied over a 9-point,3-fold dilution series with 5,000 nM typically being the highest dose.Cell culture and treatment were carried out in a humidified 37° C., 5%CO₂ incubator. Treated cells were stimulated with 150 ng/ml recombinanthuman SCF for 4 minutes to induce activation of c-KIT. Cells were lysedin a manner which preserves phosphoproteins, and the lysate was analyzedby ELISA (R&D Systems, Human Phospho-SCF R DuoSet IC DYC3527), in whichtotal c-KIT protein in the lysate is captured and phosphotyrosineresidues of c-Kit are detected. A standard curve, made using purifiedphospho-SCF R protein, was used to quantify phospho-c-KIT incompound-treated wells. A standard 4-parameter logistic model was fit tothe inhibitor dose response curves, with the IC₅₀ being defined as theconcentration of inhibitor giving 50 percent of control (POC).

Table A provides averaged IC₅₀ values for compounds of Formula I whentested in the assays described in Examples A, B, C and/or D.

TABLE A PDGFR PDGFR cFMS cKIT Cell LICOR Cell ELISA Cell ELISA CellELISA Ex. # IC₅₀ IC₅₀ IC₅₀ IC₅₀ 1 12.9 29.7 16.1 53.3 2 23.7 9.4 27.741.1 3 10.0 137.8 70.4 176.1 4 10.7 27.9 29.4 81.6 5 22.0 20.5 27.9 82.86 6.3 33.5 40.9 57.0 7 N/A 40.9 20.8 43.7 8 32.6 N/A 33.6 122.1 9 166.2N/A 21.2 142.7 10 40.8 N/A 25.3 141.1 11 46.5 N/A 26.2 156.9 12 44.0 N/A11.4 50.4 13 11.3 N/A 12.9 76.3 14 36.6 37.7 20.6 96.4 15 46.2 N/A 12.060.6 16 103.0 28.1 13.9 34.8 17 312.6 85.0 11.0 54.2 18 673.8 59.9 10.281.8 19 247.0 43.2 9.4 39.1 20 N/A 55.9 10.8 76.1 21 N/A 123.5 12.0 46.622 N/A 17.6 6.7 5.2 23 N/A 238.7 21.1 65.7 24 N/A 14.1 6.8 6.4 25 18.041.8 23.8 51.4 26 63.2 29.6 13.7 27.9 27 72.6 69.5 13.8 36.2 28 9.9 5.914.0 35.5 29 44.1 N/A 28.6 161.5 30 17.4 N/A 17.6 65.3 31 N/A 335.1101.5 67.1 32 N/A 66.5 24.2 42.4 33 N/A 65.8 41.5 22.6 34 1667 1000 N/AN/A 35 N/A 430.7 19.4 923.6 36 N/A 65.6 12.0 118.9 37 N/A 101.7 52.462.0 38 N/A 252.9 15.4 336.8 39 N/A 68.0 35.7 187.6 40 N/A 37.2 55.895.0 41 N/A 19.6 97.1 87.2 42 4801 1000 N/A N/A 43 N/A 84.5 23.4 58.9 44794.5 115.5 22.7 63.4 45 113.4 347.4 13.4 165.5 46 N/A 21.4 22.4 42.5 476.5 74.9 15.9 48.5 48 47.7 N/A 13.3 45.1 49 9.7 N/A 11.8 53.5 50 N/A N/A5.8 N/A 51 N/A 394 9.9 687.3 52 N/A 1000 108.2 5000 53 N/A 1000 73.54584.5 54 N/A 290.6 8.8 386.9 55 305.1 N/A 40.1 N/A 56 N/A 1000 32.11161.6 57 N/A 657.5 40.2 1268.0 58 914.8 N/A 21.9 6874.1 59 19.3 N/A19.4 1493.9 60 5000 N/A 35.6 4562.6 61 222.0 N/A 58.1 527.0 62 N/A 885.8257.1 2446.1 63 N/A 1000 47.0 5000 64 94.1 N/A 9.7 1007.3 65 212.1 N/A8.5 646.6 66 4.8 18.3 10.2 30.7 67 10.3 N/A 10.0 60.6 68 23.2 N/A 5.076.9 69 N/A N/A 8.2 N/A 70 N/A 99.2 5.1 146.0 71 N/A 273.7 7.6 454.6 723163.6 N/A 24.2 7013.7 73 N/A 1000 63.6 5000 74 N/A N/A 79.5 N/A 75 N/A1000 426.6 5000 76 N/A 1000 47.0 5000 77 N/A 1000 78.1 5000 78 3425.5N/A 17.3 4069.4 79 N/A 1000 56.9 4324.1 80 174.0 N/A 8.2 5702.6 816444.4 N/A 135.9 4444.7 82 N/A 309.2 122.1 458.2 83 N/A 1000 537.9 500084 N/A 1000 734.0 5000 85 401.2 N/A 10.4 303.0 86 116.8 N/A 7.0 313.7 8777.7 N/A 4.9 371.6 88 180.1 N/A 15.6 510.3 89 844.9 N/A 7.3 1047.5 905.0 N/A 9.8 25.8 91 10.9 22.2 4.4 30.1 92 N/A 137.3 26.0 204.9 93 6.0N/A 842.3 6.4 94 65.0 N/A 46.9 94.8 95 74.3 N/A 31.4 78.2 96 14.6 N/A115.0 3.8 97 9.6 N/A 10.4 25.7 98 5.7 N/A 26.3 4.9 99 6.4 N/A 5.6 11.4100 6.0 N/A 23.6 3.3 101 23.7 N/A 43.6 30.5 102 17.6 N/A 26.0 94.9 1032.7 N/A 7.3 7.2 104 78.4 N/A 33.7 397.8 105 2.6 N/A 3.3 2.7 106 557.9N/A 158.5 747.7 107 158.3 N/A 44.8 123.2 108 142.1 N/A 66.7 181.2 109N/A 26.3 10.5 8.4 110 1000 N/A 379.7 168.5 111 449.0 N/A 149.8 451.4 11216.7 N/A 33.7 68.9 113 289.1 N/A 120.6 331.4 114 9.3 N/A 24.6 8.7 1156.8 N/A 24.1 13.4 116 54.0 N/A 184.8 191.7 117 N/A 54.8 167.9 124.6 118177.6 N/A 309.5 580.9 119 17.4 N/A 26.3 23.0 120 7.7 N/A 34.4 14.5 12113.3 N/A 20.9 73.1 122 49.5 N/A 131.2 60.9 123 N/A 161.9 378.5 255.0 1246.9 N/A 8.3 9.5 125 2.1 N/A 12.5 19.8 126 34.5 N/A 27.4 22.2 127 1.7 N/A14.9 67.8 128 N/A N/A 130.9 N/A 129 117.5 N/A 80.0 123.6 130 114.0 N/A441.9 N/A 131 681.8 N/A 992.6 5000 132 170.0 N/A 134.4 603.6 133 1000N/A 99.1 N/A 134 2.4 N/A 3.1 11.0 135 362.1 N/A 228.0 395.6 136 1000 N/A20.7 54.1 137 2.0 N/A 3.1 3.1 138 1.9 N/A 8.5 3.9 139 1.3 N/A 10.6 7.9140 2.5 N/A 3.1 4.8 141 1.6 N/A 4.4 3.7 142 14.2 N/A 6.9 6.1 143 12.0N/A 4.8 58.9 144 21.9 N/A 57.8 36.5 145 13.0 N/A 20.5 55.9 146 109.4 N/A58.2 36.9 147 399.2 N/A 72.6 93.1 148 993.9 N/A 93.1 188.8 149 1.0 N/A2.2 4.8 150 1.7 N/A 4.6 14.4 151 9.0 N/A 44.8 37.3 152 296.3 N/A 117.5164.7 153 5.0 N/A 14.8 9.5 154 186.4 N/A 142.7 150.3 155 N/A 282.1 113.876.2 156 5.7 N/A 5.7 12.5 157 N/A 275.1 104.5 232.5 158 2403.1 N/A 534.82102.3 159 64.3 N/A 26.6 9.8 160 713.5 N/A 132.3 867.6 161 N/A 236.458.9 43.1 N/A = Not available

Preparation of Synthetic Intermediates Preparation A Ethyl7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate

Step A: Preparation of4-(2-(4-Methylpiperazin-1-yl)ethoxy)pyridin-2-amine

Sodium hydride (60% in mineral oil; 43.56 g; 1089 mmol) was added to a 3L reaction flask under nitrogen. A mechanical stirrer and thermocouplewas attached. Dry diglyme (400 mL) was added. A solution of2-(4-methylpiperazin-1-yl)ethanol (157 g; 1089 mmol) in diglyme (450 mL)was added slowly with stirring. The mixture was stirred with warming to40° C. for 1 hour. 4-Chloropyridin-2-amine (70.0 g; 544.5 mmol) wasadded as a solid. The mixture was heated to 80° C. with stirring untileffervescence had ceased. The temperature was increased to 157° C. for16 hours. The mixture was allowed to cool and diluted with water (500mL). THF (1000 mL) was added followed by sodium chloride (sufficient tosaturate the aqueous phase). The phases were separated and the aqueousphase was further extracted with THF (3×800 mL). Additional water wasadded as required to aid in phase separation. The combined organicphases were dried with sodium sulfate (1000 g) for 16 hours andfiltered. The solvent was removed under vacuum to remove the majority ofthe THF. The solution was filtered through Celite to remove fineparticulates rinsing with diglyme. The diglyme was removed under vacuum(10 mm Hg vacuum, with the bath temperature increased to 60° C.). Theresidue was placed under high vacuum for 1 hour and then triturated withether (400 mL). The resulting solids were collected by filtration,washed with ether and dried under vacuum to give the product (100.4 g)as an off white solid.

Step B: Preparation of4-(2-(4-Methylpiperazin-1-yl)ethoxy)pyridin-2-amine

Potassium 2-Chloro-3-ethoxy-3-oxoprop-1-en-1-olate (120 g, 635 mmol) wassuspended (through vigorous magnetic stirring) in 1800 mL of ether and6N sulfuric acid (53 mL, 317 mmol) was added slowly. The lower aqueoussuspension was sampled periodically for acidity. Additional water (100mL) was added to aid in phase separation. When the pH of the lower(aqueous) phase dropped below 3, the ether phase was separated. Theaqueous phase was further extracted with ether (200 mL). The combinedether phases were dried over sodium sulfate and magnesium sulfate for 10minutes. The solution was filtered and concentrated under reducedpressure, with the temperature not exceeding 20° C. An off-whitesemi-solid (100 g) was obtained. This was dissolved in absolute ethanol(800 mL). 4-(2-(4-Methylpiperazin-1-yl)ethoxy)pyridin-2-amine(Preparation C; 75 g, 317 mmol) was added, and the mixture was heatedunder nitrogen at 65° C. for 18 hours. The mixture was cooled to ambienttemperature and the resulting suspension was evaporated to dryness underreduced pressure. The resulting solids were triturated with THF,collected by filtration and then dried under vacuum. The material (anHCl salt) was mixed with water (1 L) and ethanol (500 mL). Sodiumbicarbonate (50 g) was added and the mixture was stirred for 18 hours.The suspension was evaporated to dryness under vacuum. The solids wereextracted with a large volume of ethyl acetate (4 L) and THF (1 L) untilno further product was extracted. The organic solution was further driedwith sodium sulfate and magnesium sulfate, filtered and concentratedunder vacuum to give a solid. The material was triturated with ether(500 mL) and the solids were collected by filtration and dried undervacuum to afford the desired product (86.2 g) as an off-white solid.

Preparation B Potassium (E)-2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate

A mixture of ethyl 2-chloroacetate (220.8 g; 1802 mmol) and ethylformate (133.5 g; 1802 mmol) was added slowly to a suspension ofpotassium t-butoxide (202.2 g; 1802 mmol) in diisopropyl ether (2000 mL)at 0° C. (maintaining the temperature <20° C.) with mechanical stirring.The mixture was stirred at ambient temperature for 24 hours. The solidswere collected by filtration and washed with diisopropyl ether (500 mL)and acetonitrile (2×1500 mL). The material was dried under vacuum togive the product (270 g) which was used without further purification.

Preparation C ethyl 6-isopropylpicolinate

Step A: Preparation of tert-butyl 4-fluoropyridin-2-ylcarbamate

A flask was charged with 2-chloro-4-fluoropyridine (20 g, 152 mmol),tert-butyl carbamate (89 g, 760 mmol), tris(dibenzylideneacetone)dipalladium (1.39 g, 1.52 mmol), X-PHOS (1.48 g, 3.10 mmol), cesiumcarbonate (99 g, 588 mmol), and tetrahydrofuran (500 mL) under anatmosphere of dry nitrogen. The mixture was heated at reflux undernitrogen for 7 hours. A further 1 equivalent of cesium carbonate wasadded and the reaction was heated a further 7 hours. The mixture wascooled to ambient temperature, filtered through Celite and washed withethyl acetate. The filtrate was partitioned between saturated sodiumbicarbonate and ethyl acetate. The aqueous phase was extracted twicewith ethyl acetate. The combined organic phases were washed with brineand dried with sodium sulfate, concentrated under vacuum, and purifiedby column chromatography to give tert-butyl4-fluoropyridin-2-ylcarbamate as a pale yellow solid (22.6 g).

Step B: Preparation of 4-fluoropyridin-2-amine

A flask was charged with tert-butyl 4-fluoropyridin-2-ylcarbamate (3.5g, 16.5 mmol) and dichloromethane (100 mL). The mixture was cooled to0-5° C. using an ice/water bath. Trifluoroacetic acid (75 mL) was addedslowly with continued stirring. The mixture was stirred at ambienttemperature for 16 hours. The mixture was concentrated under vacuumbefore partitioning between saturated sodium bicarbonate and ethylacetate. The aqueous layer was washed with ethyl acetate twice. Thecombined organic phases were washed with brine and dried with sodiumsulfate before concentrating under vacuum to give4-fluoropyridin-2-amine as a pale yellow solid (1.76 g).

Step C: Preparation of ethyl7-fluoroimidazo[1,2-a]pyridine-3-carboxylate

4-Fluoropyridin-2-amine (10.0 g, 48.0 mmol) was mixed with ethanol (40mL) in a reaction flask, under an atmosphere of dry nitrogen. A solutionof ethyl 2-chloro-3-oxopropanoate (5% in benzene, 178 mL (commercialsolution from Toronto Research Chemicals Inc.) was added. The mixturewas heated to 60° C. under nitrogen for 4 hours. After allowing themixture to cool the solvent was removed under vacuum to give a brownsolid. The solid was mixed with ethyl acetate (300 mL) and sodiumbicarbonate solution (75 mL) and stirred to dissolve. The phases wereseparated and the bicarbonate solution was extracted further with ethylacetate (75 mL). The combined ethyl acetate extracts were dried oversodium sulfate, filtered and concentrated under vacuum to give a solid.The crude material was dissolved in ethyl acetate and passed through ashort column of silica, eluting with ethyl acetate. Factions containingthe desired product were concentrated to give ethyl7-fluoroimidazo[1,2-a]pyridine-3-carboxylate as a white solid (13 g).

Step D: Preparation of ethyl 6-chloropicolinate

A flask equipped with a condenser was charged with 6-chloropicolinicacid (23.5 g, 149 mmol), 100 mL of ethanol and 400 mL of toluene. Tothis was added 4 mL of sulfuric acid and the mixture was warmed toreflux for three hours, and then allowed to cool to ambient temperature.The reaction mixture was concentrated under reduced pressure and theresulting oil was taken up in 200 mL of ethyl acetate, washed with 10%aqueous potassium carbonate, dried over sodium sulfate and concentratedunder reduced pressure to give 26 g of ethyl 6-chloropicolinate (94%).

Step E: Preparation of ethyl 6-(prop-1-en-2-yl)picolinate

A first flask was charged with 1,4-dioxane/H₂O (50 mL/10 mL). The flaskwas cooled to 0° C. and vacuum was applied for 20 minutes. A secondflask was charged with ethyl 6-chloropicolinate (4.200 g, 22.63 mmol),potassium trifluoro(prop-1-en-2-yl)borate (4.353 g, 29.42 mmol),potassium carbonate (4.378 g, 31.68 mmol), diacetoxypalladium (0.1524 g,0.6789 mmol) and sodium2′-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate (0.6959 g,1.358 mmol). The second flask was also evacuated with vacuum and backfilled with N₂ for 3 times. The cold degassed dioxane/H₂O was then addedto the second flask, which was evacuated with vacuum and back filledwith argon 5 times. The reaction mixture was heated to 80° C. for 3hours. The reaction was cooled to ambient temperature and concentratedunder reduced pressure. The residue was then diluted with EtOAc (200mL). The organic layer was washed with saturated NaHCO₃, dried (Na₂SO₄)and concentrated to give a quantitative yield of ethyl6-(prop-1-en-2-yl)picolinate, which was used in the next step withoutfurther purification.

Step F: Preparation of ethyl 6-isopropylpicolinate

To ethyl 6-(prop-1-en-2-yl)picolinate (4.63 g, 24.2 mmol) in EtOH (50mL) was added Pd/C (0.61 g, 0.573 mmol). The reaction mixture was purgedwith nitrogen three times and then with hydrogen three times. A hydrogenballoon was applied to the reaction for three hours. The reaction wasthen purged with N₂, filtered through Celite and washed with EtOH (100mL). Solvent was removed under reduced pressure to give 4.36 g (93%) ofethyl 6-isopropylpicolinate.

Preparation D1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine

Step A: Preparation of (6-isopropylpyridin-2-yl)methanol)

Ethyl 6-isopropylpicolinate (prepared as in Preparation C; 75 g, 0.39mol) was dissolved in 1.5 liters of dry THF, chilled to 0° C. andlithium aluminum hydride (0.39 L, 0.39 mol, 1M in THF) was added slowlyover a 20 minute period. The resulting dark solution was stirred at 0°C. for 30 minutes, then allowed to warm to ambient temperature. TLCshowed complete consumption of starting material. The reaction mixturewas chilled to 0° C. and quenched carefully by the addition of sodiumsulfate decahydrate until no gas evolution was observed. A thick mixtureresulted. Celite and ether (about 200 mL) were added and the reactionmixture was filtered. The filtrate was concentrated under reducedpressure to give 32 g of brown oil. The filter cake was slurried inIPA/EtOAc overnight and filtered to give an additional 8 g of product(68%).

Step B: Preparation of 2-(chloromethyl)-6-isopropylpyridinehydrochloride

6-Isopropylpyridin-2-yl)methanol (40 g, 0.265 mol) was dissolved in 500mL of dry dichloromethane and chilled to 0° C. To this was added thionylchloride (37.8 g, 0.317 mol) and the mixture was stirred for one hour.The reaction mixture was then concentrated under reduced pressure togive a quantitative yield of 2-(chloromethyl)-6-isopropylpyridinehydrochloride.

Step C: Preparation of 3-bromo-4-nitro-1H-indazole

To a flask equipped with a mechanical stirrer was added sodium acetate(26.4 g, 0.306 mol), 4-nitro-1H-indazole (50 g, 0.306 mol), 300 mL ofacetic acid and 300 mL of chloroform. Bromine (51.4 g, 0.322 mol) in 60mL of acetic acid was added to the reaction mixture over 3.5 hours,while the temperature was kept under 25° C. The reaction mixture wasstirred for two hours, then concentrated under reduced pressure. Water(500 mL) was added to the resulting solids. The solids were collected byfiltration, washed with 500 mL of water, and dried under vacuum to give68 g (92%) of 3-bromo-4-nitro-1H-indazole.

Step D: Preparation of3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole

A flask was charged with 3-bromo-4-nitro-1H-indazole (64 g, 0.264 mol),2-(chloromethyl)-6-isopropylpyridine hydrochloride (55 g, 0.264 mol),powdered potassium carbonate (91 g, 0.661 mol), and 500 mL of DMF. Thismixture was warmed to 35° C. for 72 hours, then poured into 2 liters ofcold water, upon which a tan solid precipitated. After stirring for 20minutes, the solids were collected by filtration and dried under vacuumto give 91 g (92%) of3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole.

Step E: Preparation of1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole

A 3 liter heavy walled reaction flask was charged with dioxane (1liter), 3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole(90 g, 0.24 mol), methyl boronic acid (72 g, 1.20 mol), Pd(PPh₃)₄(9.7 g,0.0084 mol), potassium carbonate (99.5 g, 0.719 mol), followed by 200 mLof water. This mixture was purged with argon for 10 minutes, flasksealed and heated to 120° C. for 16 hours. Another 1.5 mol % ofPd(PPh₃)₄ was added followed by another 2 equivalents of methyl boronicacid, and the mixture warmed to 120° C. for 24 hours. The mixture wasdiluted with water and extracted with EtOAc. The combined organicextracts were dried over sodium sulfate and concentrated. Columnchromatography (5% ethyl acetate/hexane to 10% ethyl acetate/hexane)gave 54 g (73%) of1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole as anorange/yellow solid.

Step F: Preparation of1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine

A flask equipped with an overhead stirrer and condenser was charged with1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole (25 g,0.081 mol) and 150 mL of ethanol, followed by 45 g (0.805 mol) of ironpowder. An equal amount of saturated ammonium chloride solution wasadded and the mixture was brought to 80° C. After 5 hours of heating,the mixture was allowed to cool to ambient temperature, diluted withwater (500 mL) and filtered through GF/F filter paper multiple times toremove the iron and iron salts. The filtrate was extracted with EtOAc,dried over sodium sulfate and concentrated under reduced pressure.Column chromatography (1:1 ethyl acetate/hexane to 100% ethyl acetate)afforded 12.6 g (56%) of1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine.

EXAMPLES Example 1N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

1-((6-Isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine(Preparation D; 0.673 g, 2.40 mmol) and ethyl7-fluoroimidazo[1,2-a]pyridine-3-carboxylate (Step C, 0.500 g, 2.40mmol) were dissolved in dry THF (24 mL) and chilled to 0° C. LiHMDS(5.28 mL, 5.28 mmol, 1M in THF) was added by syringe over a five-minuteperiod. Once the addition was complete, the reaction mixture was removedfrom the cooling bath and allowed to warm to ambient temperature. Themixture was quenched with saturated ammonium chloride solution andextracted with EtOAc. The combined organic extracts were washed withsaturated sodium bicarbonate solution, dried over sodium sulfate andconcentrated. The crude material was purified by column chromatography(100% ethyl acetate) to afford 775 mg (73%) of7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide.

Step B: Preparation ofN-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxamide

7-Fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(0.250 g, 0.565 mmol), 2-morpholinoethanol (0.371 g, 2.82 mmol), andpotassium t-butoxide were combined in t-BuOH in a reaction tube. Thetube was sealed and heated to 95° C. for 16 hours. After cooling toambient temperature, the mixture was diluted with water and extractedwith EtOAc. The combined organic extracts were with 10% aqueouspotassium carbonate, dried over sodium sulfate, and concentrated. Theresulting crude product was triturated with ether to give 165 mg (53%)ofN-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxamideas a tan solid. MS (APCI), positive scan, m/z=554.1 (M+H).

Example 27-(2-(4-Ethylpiperazin-1-yl)ethoxy)-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 2-(4-ethylpiperazin-1-yl)ethanol

1-Ethylpiperazine (5.0 g, 43.8 mmol) was dissolved in 90 mL ofacetonitrile, followed by the addition of powdered potassium carbonate(18.2 g, 131 mmol), and 2-bromoethanol (10.9 g, 87.6 mmol). This mixturewas warmed to reflux for 16 hours, cooled to ambient temperature, andfiltered. The filtrate was concentrated under reduced pressure andpurified by column chromatography (10% MeOH/DCM/0.5% NH₄OH) to give 5.4g (78%) of 2-(4-ethylpiperazin-1-yl)ethanol as a light yellow oil.

Step B: Preparation of7-(2-(4-ethylpiperazin-1-yl)ethoxy)-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared as in Example 1, Step B, substituting2-(4-ethylpiperazin-1-yl)ethanol for 2-morpholinoethanol, to give thetitle compound (22%). MS (APCI), positive scan, m/z=581.1 (M+H).

Example 37-(2-(2,6-diazaspiro[3.3]heptan-2-yl)ethoxy)-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamidetrihydrochloride

Step A: Preparation of tert-butyl6-(2-hydroxyethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

Prepared as in Example 2, Step A, substituting tert-butyl2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxalate for1-ethylpiperazine to give the title compound (36%).

Step B: Preparation of tert-butyl6-(2-(3-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridin-7-yloxy)ethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate:Prepared as in Example 1, Step B, substituting tert-butyl6-(2-hydroxyethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate for2-morpholinoethanol, to give 0.8 g (33%) of the title compound.

Step C: Preparation of7-(2-(2,6-diazaspiro[3.3]heptan-2-yl)ethoxy)-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamidetrihydrochloride: tert-Butyl6-(2-(3-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridin-7-yloxy)ethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(0.075 g, 0.113 mmol) was dissolved in 2 mL of 1:1 DCM/MeOH and 4MHCl/dioxane (0.282 mL, 1.13 mmol) was added. The mixture was stirred atambient temperature for 4 hours, then concentrated under reducedpressure. The resulting residue was triturated with DCM and the solidswere collected by filtration to give 57 mgs (75%) of the title compound.MS (APCI), positive scan, m/z=567.1 (M+H).

Example 4N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of2-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)ethanol

tert-Butyl-6-(2-hydroxyethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(0.620 g, 2.56 mmol) was dissolved in dry THF (13 mL) and chilled to 0°C. Lithium aluminum hydride (7.68 mL, 7.68 mmol, 1M in THF) was added bysyringe. Once addition was complete, the mixture was brought to refluxfor 16 hours. The reaction was cooled to 0° C., quenched with 291 μL ofwater, 291 μL of 15% aq. NaOH, and 873 μL of water, stirred vigorouslyfor two hours, and then filtered. The filtrate was concentrated underreduced pressure to give 268 mgs (67%) of the title compound.

Step B: Preparation ofN-(1-((6-isoproplpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared as in Example 1, Step B, substituting2-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)ethanol for2-morpholinoethanol, to give the title compound (20%). MS (APCI),positive scan, m/z=580.6, 581.7 (M+H).

Example 57-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethoxy)-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethanol

Prepared as in Example 2, Step A, substituting2-oxa-6-azaspiro[3.3]heptane oxalate for 1-ethylpiperazine to give thetitle compound (17%).

Step B: Preparation of7-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethoxy)-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared as in Example 1, Step B, substituting2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethanol for 2-morpholinoethanol, togive the title compound (50%). MS (APCI), positive scan, m/z=566.1(M+H).

Example 67-(2-(4-Isopropylpiperazin-1-yl)ethoxy)-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared as in Example 1, Step B, substituting2-(4-isopropylpiperazin-1-yl)ethanol for 2-morpholinoethanol, to givethe title compound (55%). MS (APCI), positive scan, m/z=595.2 (M+H).

Example 7N-(1-((6-Isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of (3R,5S)-tert-butyl3,4,5-trimethylpiperazine-1-carboxylate

(3R,5S)-tert-Butyl 3,5-dimethylpiperazine-1-carboxylate (1.50 g, 7.00mmol) was dissolved in 70 mL of methanol. To this was added 37% aqueousformaldehyde (1.17 mL, 14.0 mmol) and formic acid (1.14 mL, 24.5 mmol).The reaction mixture was heated to 70° C. for 24 hours, thenconcentrated under reduced pressure. The resulting oil was taken up inEtOAc, washed with 10% aqueous potassium carbonate, dried over sodiumsulfate and concentrated to give 1.17 g (73%) of the title compound.

Step B: Preparation of (2S,6R)-1,2,6-trimethylpiperazine dihydrochloride

(3R,5S)-tert-butyl 3,4,5-trimethylpiperazine-1-carboxylate (1.17 g, 5.12mmol) was dissolved in 50 mL of EtOAc and chilled to 0° C. HCl gas wasbubbled through the solution for 20 minutes, and then the reaction flaskcapped securely and the mixture stirred at ambient temperature for 16hours. The excess HCl gas was purged from the mixture with a steadystream of nitrogen gas and the reaction mixture was concentrated underreduced pressure to give 1 g (97%) of the title compound.

Step C: Preparation of 2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)ethanol

Prepared according to Example 2, Step A, substituting(2S,6R)-1,2,6-trimethylpiperazine di-hydrochloride for 1-ethylpiperazineto give 0.856 g (100%) of the title compound.

Step D: Preparation of ethyl7-chloroimidazo[1,2-a]pyridine-3-carboxylate

To a flask equipped with a reflux condenser, mechanical stirring, andinternal temperature probe was added potassium2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (58.70 g, 311.1 mmol) followedby 200 mL of EtOH. Aqueous hydrogen chloride (4.862 ml, 15.56 mmol) inEtOH was added to the slurry. The slurry was stirred for about 15minutes, and then 4-chloropyridin-2-amine (20.00 g, 155.6 mmol) wasadded, and the mixture was warmed to 70° C. After about one hour, anadditional 2 equivalents of 3.2 M aqueous HCl were added and the mixturestirred at 70° C. for 16 hours. An additional 30 g of potassium2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate were added and the mixture wasstirred at 70° C. for 2 hours. The mixture was cooled to ambienttemperature and 500 mL of water added, followed by pH adjustment to 11with 10% aqueous sodium carbonate. After stirring for several hours, theprecipitated solids were collected by filtration and dried under vacuumto give 31 g (88%) of the title compound.

Step E: Preparation of7-chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1, Step A, substituting ethyl7-chloroimidazo[1,2-a]pyridine-3-carboxylate for ethyl7-fluoroimidazo[1,2-a]pyridine-3-carboxylate to give the title compound(56%).

Step F: Preparation ofN-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

A pressure tube was charged with7-chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(0.500 g, 1.09 mmol), 2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)ethanol(0.375 g, 2.18 mmol), crushed potassium hydroxide (0.306 g, 5.45 mmol)in 10 mL of DMSO. The tube was sealed and heated to 95° C. for 16 hours,then allowed to cool to ambient temperature. The mixture was dilutedwith water and extracted with EtOAc. The combined organic extracts werewashed with brine, dried over sodium sulfate, and concentrated underreduced pressure. Column chromatography (10% MeOH/DCM/0.5% NH₄OH)followed by trituration with methyl t-butyl ether afforded 42 mgs (6%)of the title compound. MS (APCI), positive scan, m/z=595.1 (M+H).

Example 8N-(1-((1-Isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of ethyl1-isopropyl-5-methyl-1H-pyrazole-3-carboxylate

To ethyl 2,4-dioxopentanoate (20.1 g, 127 mmol) in acetic acid (100 mL)at 0° C. was added isopropylhydrazine (9.42 g, 127 mmol) dropwise. Thecold bath was removed and the reaction mixture was stirred for 2 hours.The reaction mixture was diluted with EtOAc/H₂O (300 mL/100 mL). Theorganic layer was washed with saturated NaHCO₃ aqueous solution (100mL), H₂O (50 mL) and brine (50 mL). The organic layer was dried (Na₂SO₄)and concentrated. The residue was purified by silica gel flashchromatography (1:2 EtOAc/hexane) to give 7.8 g (31%) of the titlecompound.

Step B: Preparation of (1-isopropyl-5-methyl-1H-pyrazol-3-yl)methanol

To ethyl 1-isopropyl-5-methyl-1H-pyrazole-3-carboxylate (7.68 g, 39.1mmol) in THF (50 mL) at 0° C. was added LAH (1.49 g, 39.1 mmol). Thecold bath was removed, and the reaction mixture was stirred for 2 hours,and then quenched carefully with sodium sulfate decahydrate. Thereaction mixture was filtered through Celite and washed with Et₂O. Thefiltrate was concentrated under reduced pressure to give 5.3 g (88%) ofthe title compound.

Step C: Preparation of 3-(chloromethyl)-1-isopropyl-5-methyl-1H-pyrazolehydrochloride

Prepared according to Preparation D, Step B, substituting(1-isopropyl-5-methyl-1H-pyrazol-3-yl)methanol forisopropylpyridin-2-yl)methanol to give 7.1 g (99%) of the titlecompound.

Step D: Preparation of3-bromo-1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-4-nitro-1H-indazole

Prepared according to Preparation D, Step D, substituting3-(chloromethyl)-1-isopropyl-5-methyl-1H-pyrazole hydrochloride for2-(chloromethyl)-6-isopropylpyridine hydrochloride to give 9.12 g (71%)of the title compound.

Step E: Preparation of1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-4-nitro-1H-indazole

A flask was charged with 1,4-dioxane/H₂O (30 mL/5 mL). The flask wascooled to 0° C. and vacuum was applied for 20 minutes. A second flaskwas charged with3-bromo-1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-4-nitro-1H-indazole(1.95 g, 5.16 mmol), K₂CO₃ (2.85 g, 20.6 mmol), diacetoxypalladium(0.0579 g, 0.258 mmol), methylboronic acid (0.926 g, 15.5 mmol) andsodium 2′-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate(0.264 g, 0.516 mmol). The second flask was evacuated with and backfilled with nitrogen three times. The cold degassed dioxane/H₂O wasadded to the second flask, which was evacuated and back filled withargon 5 times. The reaction mixture was heated to 80° C. for 3 hours.The reaction was cooled to ambient temperature and filtered, andconcentrated under reduced pressure. The residue was diluted with EtOAc(200 mL). The organic layer was washed with saturated NaHCO₃ (30 mL),dried (Na₂SO₄) and concentrated to give 1.34 g (83%) of the titlecompound, which was used in the next step without further purification.

Step F: Preparation of1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-amine

Prepared according to Preparation D, Step F, substituting1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-4-nitro-1H-indazolefor 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole togive 0.86 g (72%) of the title compound.

Step G: Preparation of7-fluoro-N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1, Step A, substituting1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-aminefor 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine, togive 0.245 g (60%) of the title compound.

Step H: Preparation ofN-(1-((1-Isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according Example 1, Step B, substituting7-fluoro-N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamidefor7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand 2-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)ethanol for2-morpholinoethanol to give 23 mg (25%) of the title compound. MS(APCI), positive scan, m/z=583.3 (M+H).

Example 9N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according Example 1, Step B, substituting7-fluoro-N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Example 8, Steps A-G) for7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand 2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)ethanol for2-morpholinoethanol to give 11 mg (6%) of the title compound. MS (APCI),positive scan, m/z=598.2 (M+H).

Example 10N-(1-((1-Isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according Example 1, Step B, substituting7-fluoro-N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Example 8, Steps A-G) for7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand 2-(4-isopropylpiperazin-1-yl)ethanol for 2-morpholinoethanol to give15 mg (11%) of the title compound. MS (APCI), positive scan, m/z=598.1(M+H).

Example 11N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-methyl-1,4-diazepan-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of tert-butyl4-(2-hydroxyethyl)-1,4-diazepane-1-carboxylate

Prepared according to Example 2, Step A, substituting tert-butyl1,4-diazepane-1-carboxylate for 1-ethylpiperazine to give 0.845 g (46%)of the title compound.

Step B: Preparation of 2-(4-methyl-1,4-diazepan-1-yl)ethanol

Prepared according to Example 4, Step A, substituting tert-butyl4-(2-hydroxyethyl)-1,4-diazepane-1-carboxylate for tert-Butyl6-(2-hydroxyethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate to give0.220 g (40%) of the title compound.

Step C: Preparation ofN-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-methyl-1,4-diazepan-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according Example 1, Step B, substituting7-fluoro-N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Example 8, Steps A-G) for7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand 2-(4-methyl-1,4-diazepan-1-yl)ethanol for 2-morpholinoethanol togive 18 mgs (11%) of the title compound. MS (APCI), positive scan,m/z=584.1 (M+H).

Example 12N-(1-((2-isopropylthiazol-4-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 4-(chloromethyl)-2-isopropylthiazolehydrochloride

Prepared according to Preparation D, Step B, substituting(2-isopropylthiazol-4-yl)methanol for isopropylpyridin-2-yl)methanol togive (81%) of the title compound (81%).

Step B: Preparation of4-((3-bromo-4-nitro-1H-indazol-1-yl)methyl)-2-isopropylthiazole

Prepared according to Preparation D, Step D, substituting4-(chloromethyl)-2-isopropylthiazole hydrochloride for2-(chloromethyl)-6-isopropylpyridine hydrochloride to give the finalproduct (78%).

Step C: Preparation of2-isopropyl-4-((3-methyl-4-nitro-1H-indazol-1-yl)methyl)thiazole

Prepared according to Preparation D, Step E, substituting4-((3-bromo-4-nitro-1H-indazol-1-yl)methyl)-2-isopropylthiazole for3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole to givethe title compound (79%).

Step D: Preparation of1-((2-isopropylthiazol-4-yl)methyl)-3-methyl-1H-indazol-4-amine

Prepared according to Preparation D, Step F, substituting2-isopropyl-4-((3-methyl-4-nitro-1H-indazol-1-yl)methyl)thiazole for1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole to givethe title compound (76%).

Step E: Preparation of7-fluoro-N-(1-((2-isopropylthiazol-4-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1, Step A, substituting1-((2-isopropylthiazol-4-yl)methyl)-3-methyl-1H-indazol-4-amine for1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine, to givethe title compound (53%).

Step F: Preparation ofN-(1-((2-isopropylthiazol-4-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according Example 1, Step B, substituting7-fluoro-N-(1-((2-isopropylthiazol-4-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Example 12, Steps A-E) for7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand 2-(4-methyl-1,4-diazepan-1-yl)ethanol for 2-morpholinoethanol togive the title compound (78%). MS (APCI), positive scan, m/z=573.1(M+H).

Example 13N-(1-((2-isopropylthiazol-4-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according Example 1, Step B, substituting7-fluoro-N-(1-((2-isopropyithiazol-4-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Example 12, Steps A-E) for7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand 2-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)ethanol (Example 4) for2-morpholinoethanol to give the title compound (41%). MS (APCI),positive scan, m/z=585.1 (M+H).

Example 147-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethoxy)-N-(1-((2-isopropylthiazol-4-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according Example 1, Step B, substituting7-fluoro-N-(1-((2-isopropylthiazol-4-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Example 12, Steps A-E) for7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand 2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethanol (Example 5) for2-morpholinoethanol to give the title compound (53%). MS (APCI),positive scan, m/z=572.0 (M+H).

Example 157-(2-(4-isopropylpiperazin-1-yl)ethoxy)-N-(1-((2-isopropylthiazol-4-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according Example 1, Step B, substituting7-fluoro-N-(1-((2-isopropylthiazol-4-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Example 12, Steps A-E) for7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand substituting 2-(4-isopropylpiperazin-1-yl)ethanol for2-morpholinoethanol to give the title compound (68%). MS (APCI),positive scan, m/z=601.1 (M+H).

Example 16N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 6-cyclopropylpicolinaldehyde

A flame dried flask was charged with dry THF (75 mL) and chilled to −78°C. To this was added n-BuLi (9.90 mL, 24.7 mmol, 2.5 M in hexanes),followed by the slow addition of a THF (25 mL) solution of the2-bromo-6-cyclopropylpyridine (4.90 g, 24.7 mmol) over a 15 minuteperiod). The mixture was stirred at −78° C. for 15 minutes, and neat DMF(2.87 mL, 37.1 mmol) was added. The mixture was stirred for 15 minutesat −78° C., then quenched with saturated ammonium chloride solution (50mL) and allowed to warm to ambient temperature. The mixture was dilutedwith water, extracted with EtOAc, dried over sodium sulfate andconcentrated to 3.5 g (96%) of an orange oil/liquid.

Step B: Preparation of (6-cyclopropylpyridin-2-yl)methanol

To 6-cyclopropylpicolinaldehyde (3.5 g, 23.8 mmol) in methanol (95 mL)chilled to 0° C. was added sodium borohydride (2.70 g, 37.8 mmol). Onceaddition was complete, the cooling bath was removed and the reactionmixture was allowed to warm to ambient temperature. The mixture wasconcentrated under reduced pressure and the resulting residue was takenup in water, extracted with EtOAc, dried over sodium sulfate andconcentrated under reduced pressure. Column chromatography (100% EtOAcas the eluent) of the crude material afforded 2.20 g (62%) of the titlecompound.

Step C: Preparation of 2-(chloromethyl)-6-cyclopropylpyridinehydrochloride

Prepared according to Preparation D, Step B, substituting(6-cyclopropylpyridin-2-yl)methanol for6-isopropylpyridin-2-yl)methanol, to give the title compound (100%).

Step D: Preparation of3-bromo-1-((6-cyclopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole

Prepared according to Preparation D, Step D, substituting2-(chloromethyl)-6-cyclopropylpyridine hydrochloride for2-(chloromethyl)-6-isopropylpyridine hydrochloride to give the finalproduct (87%).

Step E: Preparation of1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole

Prepared according to Preparation D, Step E, substituting3-bromo-1-((6-cyclopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole(Example 16, Steps A-D) for3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole to givethe title compound (70%).

Step F: Preparation of1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine

Prepared according to Preparation D, Step F, substituting1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole for1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole to givethe title compound (70%).

Step G: Preparation ofN-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1, Step A, substituting1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine for1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine, to givethe title compound (83%).

Step H: Preparation ofN-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according Example 1, Step B, substitutingN-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamidefor7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand substituting 2-(4-isopropylpiperazin-1-yl)ethanol for2-morpholinoethanol to give the title compound (48%). MS (APCI),positive scan, m/z=593.8 (M+H).

Example 17N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-ethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according Example 1, Step B, substitutingN-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide(Example 16, Steps A-G) for7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand substituting 2-(4-ethylpiperazin-1-yl)ethanol for2-morpholinoethanol to give the title compound (8%). MS (APCI), positivescan, m/z=579.1 (M+H).

Example 18N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according Example 1, Step B, substitutingN-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide(Example 16, Steps A-G) for7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideto give the title compound (64%). MS (APCI), positive scan, m/z=552.1(M+H).

Example 19N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3,3,4-trimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of tert-butyl4-(2-hydroxyethyl)-2,2-dimethylpiperazine-1-carboxylate

Prepared as in Example 2, Step A, substituting tert-butyl2,2-dimethylpiperazine-1-carboxylate for 1-ethylpiperazine to give thetitle compound (85%).

Step B: Preparation of 2-(3,3,4-trimethylpiperazin-1-yl)ethanol

Prepared according to Example 4, Step A, substituting tert-butyl4-(2-hydroxyethyl)-2,2-dimethylpiperazine-1-carboxylate for tert-Butyl6-(2-hydroxyethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate, to give thetitle compound (100%).

Step C: Preparation ofN-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3,3,4-trimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according Example 1, Step B, substitutingN-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide(Example 16, Steps A-G) for7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand 2-(3,3,4-trimethylpiperazin-1-yl)ethanol for 2-morpholinoethanol togive the title compound (19%). MS (APCI), positive scan, m/z=593.1(M+H).

Example 20N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-(2-methoxyethyl)piperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 2-(4-(2-methoxyethyl)piperazin-1-yl)ethanol

Prepared as in Example 2, Step A, substituting 2-(piperazin-1-yl)ethanolfor 1-ethylpiperazine to give the title compound (71%).

Step B: Preparation ofN-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-(2-methoxyethyl)piperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according Example 1, Step B, substitutingN-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide(Example 16, Steps A-G) for7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand 2-(4-(2-methoxyethyl)piperazin-1-yl)ethanol for 2-morpholinoethanolto give the title compound (41%). MS (APCI), positive scan, m/z=609.1(M+H).

Example 21N-(3-chloro-1-((6-cyclopropylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 3-chloro-4-nitro-1H-indazole

To a solution of sodium hydroxide (2.94 g, 73.6 mmol) in 100 mL of waterwas added 4-nitro-1H-indazole (3.00 g, 18.39 mmol), followed by sodiumhypochlorite (33.4 g, 6.15% aqueous solution). This mixture was allowedto stir at ambient temperature overnight. The mixture was acidified topH 2 with 10% aqueous HCl and extracted with 25% IPA/DCM. The combinedorganic extracts were washed with water, dried over sodium sulfate andconcentrated under reduced pressure. The resulting solids weretriturated with ether to give 1.5 g (41%) of the title compound.

Step B: Preparation of3-chloro-1-((6-cyclopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole

Prepared according to Preparation D, Step D, substituting3-chloro-4-nitro-1H-indazole for 3-bromo-4-nitro-1H-indazole and2-(chloromethyl)-6-cyclopropylpyridine hydrochloride for2-(chloromethyl)-6-isopropylpyridine hydrochloride, to give the titlecompound (72%).

Step C: Preparation of3-chloro-1-((6-cyclopropylpyridin-2-yl)methyl)-1H-indazol-4-amine

Prepared according to Preparation D, Step F, substituting3-chloro-1-((6-cyclopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole for1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole to givethe title compound (63%).

Step D: Preparation ofN-(3-chloro-1-((6-cyclopropylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1, Step A, substituting3-chloro-1-((6-cyclopropylpyridin-2-yl)methyl)-1H-indazol-4-amine for1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine to givethe title compound (19%).

Step E: Preparation ofN-(3-chloro-1-((6-cyclopropylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according Example 1, Step B, substitutingN-(3-chloro-1-((6-cyclopropylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamidefor7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand 2-(4-isopropylpiperazin-1-yl)ethanol for 2-morpholinoethanol to givethe title compound (25%). MS (APCI), positive scan, m/z=613.1 (M+H).

Example 22N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-fluoro-1H-indazol-4-yl)-7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 3-fluoro-4-nitro-1H-indazole

A microwave vial equipped with a stir bar was charged with the4-nitro-1H-indazole (1.00 g, 6.13 mmol), and Select Fluor (2.82 g, 7.97mmol) in 10 mL of acetonitrile. The mixture was heated in a microwave at100° C. for 2 hours. The mixture was diluted with EtOAc, washed with 10%aqueous potassium carbonate, dried over sodium sulfate and concentratedunder reduced pressure. Column chromatography (EtOAc) of the crudematerial afforded 820 mg (74%) of the title compound.

Step B: Preparation of1-((6-cyclopropylpyridin-2-yl)methyl)-3-fluoro-4-nitro-1H-indazole

Prepared according to Preparation D, Step D, substituting3-fluoro-4-nitro-1H-indazole for 3-bromo-4-nitro-1H-indazole and2-(chloromethyl)-6-cyclopropylpyridine hydrochloride for2-(chloromethyl)-6-isopropylpyridine hydrochloride to give the titlecompound (35%).

Step C: Preparation of1-((6-cyclopropylpyridin-2-yl)methyl)-3-fluoro-1H-indazol-4-amine

Prepared according to Preparation D, Step F, substituting1-((6-cyclopropylpyridin-2-yl)methyl)-3-fluoro-4-nitro-1H-indazole for1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole to givethe title compound (91%).

Step D: Preparation ofN-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-fluoro-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1, Step A, substituting1-((6-cyclopropylpyridin-2-yl)methyl)-3-fluoro-1H-indazol-4-amine for1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine to givethe title compound (38%).

Step E: Preparation ofN-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-fluoro-1H-indazol-4-yl)-7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according Example 1, Step B, substitutingN-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-fluoro-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamidefor7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand 2-(4-isopropylpiperazin-1-yl)ethanol for 2-morpholinoethanol to givethe title compound (35%). MS (APCI), positive scan, m/z=597.0 (M+H).

Example 23(S)—N-(3-chloro-1-((6-cyclopropylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of (S)-tert-butyl3,4-dimethylpiperazine-1-carboxylate

To a solution of (S)-tert-butyl 3-methylpiperazine-1-carboxylate (50 g,0.250 mol) in 500 mL of methanol was added formaldehyde (41.6 mL, 0.5mol, 37% aqueous solution) and formic acid (33 mL, 0.874 mol) and themixture was heated to 70° C. for 16 hours, then concentrated underreduced pressure. The resulting residue was taken up in EtOAc (500 mL),washed with 10% aqueous potassium carbonate, dried over sodium sulfateand concentrated under reduced pressure to give 54 g (100%) of the titlecompound.

Step B: Preparation of (S)-1,2-dimethylpiperazine dihydrochloride

(S)-tert-Butyl 3,4-dimethylpiperazine-1-carboxylate (54 g, 0.252 mol)was dissolved in 500 mL of EtOAc and the mixture was chilled to 0° C.HCl gas was bubbled through the solution for 20 minutes, during whichtime a white solid formed and then dissolved. The reaction vessel wascapped and allowed to stir at ambient temperature for 16 hours, duringwhich a white precipitate had formed. The mixture was purged withnitrogen for 10 minutes and the solids were collected by filtration togive 45 g (96%) of the title compound.

Step C: Preparation of (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol

Prepared according to Example 2, Step A, substituting(S)-1,2-dimethylpiperazine di-hydrochloride for 1-ethylpiperazine andsodium bicarbonate for potassium carbonate to give the title compound(64%).

Step D:(S)—N-(3-chloro-1-((6-cyclopropylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according Example 1, Step B, substitutingN-(3-chloro-1-((6-cyclopropylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide(Example 21, Steps A-D) for7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol for 2-morpholinoethanol togive the title compound (5%). MS (APCI), positive scan, m/z=599.0 (M+H).

Example 24(S)—N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-fluoro-1H-indazol-4-yl)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according Example 1, Step B, substitutingN-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-fluoro-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide(Example 22, Steps A-D) for7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol for 2-morpholinoethanol togive the title compound (15%). MS (APCI), positive scan, m/z=583.1(M+H).

Example 25(S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of ethyl7-chloroimidazo[1,2-a]pyridine-3-carboxylate

A flask equipped with a reflux condenser, mechanical stirring, and aninternal temperature probe, was charged with potassium2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (58.70 g, 311.1 mmol) followedby addition 200 mL of EtOH to form a slurry. Aqueous hydrogen chloride(4.862 mL, 15.56 mmol) in EtOH was then added to the slurry. The slurrywas stirred for about 15 minutes, and then 4-chloropyridin-2-amine(20.00 g, 155.6 mmol) was added, and the mixture was warmed to 70° C.After about one hour, an additional 2 equivalents of 3.2 M aqueous HClwere added and the mixture stirred at 70° C. for 16 hours. At thispoint, an additional 30 g of potassium2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate were added and the mixturestirred at 70° C. for 2 hours to facilitate completion of the reaction.The mixture was cooled to ambient temperature and 500 mL of water wereadded, followed by adjustment of the pH to 11 with 10% aqueous sodiumcarbonate. After stirring for several hours, the precipitated solidswere collected by filtration and dried under vacuum to give 31 g (88%)of the desired compound.

Step B: Preparation of7-chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

A round bottom flask containing ethyl7-chloroimidazo[1,2-a]pyridine-3-carboxylate (15.22 g, 67.8 mmol) and1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine(Preparation D; 19.0 g, 67.8 mmol,) in 130 mls of THF was chilled to 0°C. LiHMDS (1M in THF, 149 mls, 149 mmol) was then added by syringe overa 15 minute period. Once the addition was complete, the reaction mixturewas stirred at 0° C. for 15 minutes, and then quenched with saturatedammonium chloride (250 mls). This mixture was then extracted two timeswith EtOAc, the extracts were dried over sodium sulfate and concentratedunder reduced pressure. Column chromatography (100% EtOAc) afforded 18.6g (60%) of the title compound.

Step C: Preparation of(S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

A flask equipped with a condenser was charged with the7-chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(15.0 g, 32.68 mmol), (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol (10.34g, 65.37 mmol, Example 23), crushed KOH (9.17 g, 163.4 mmol) and 100 mLof DMSO. The mixture was heated to 95° C. for 22 hours. The mixture wasallowed to cool to ambient temperature, 350 mL of water were added andthe mixture stirred vigorously for 30 minutes. The mixture was extractedwith EtOAc, and the combined organic extracts were washed with brine and10% aqueous potassium carbonate, dried and concentrated. The resultingmaterial was purified by column chromatography (10% MeOH/DCM/0.5% NH₄OHto 15% MeOH/DCM/0.5% NH₄OH) and then triturated with ether. Theresulting solid was collected to give 10 g (53%) of the title compound.MS (APCI), positive scan, m/z=581.1 (M+H). [α]_(D)=+5.6° (c=1.0, CHCl₃).

Example 26(S)—N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamidedihydrochloride

Step A: Preparation of(S)—N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide(Example 16, Step G; 0.250 g, 0.568 mmol),(S)-2-(3,4-dimethylpiperazin-1-yl)ethanol (0.449 g, 2.84 mmol), andpotassium t-butoxide (0.382 g, 3.41 mmol) were combined in t-butanol ina pressure tube. The tube was sealed and warmed to 95° C. for 16 hours,then allowed to cool to ambient temperature. The mixture was dilutedwith water and extracted with EtOAc. The combined organic extracts werewashed with 10% aqueous potassium carbonate, dried over sodium sulfateand concentrated under reduced pressure. Column chromatography (10%MeOH/DCM/0.5% NH₄OH) of the crude material followed by trituration withether gave 102 mg (31%) of the title compound. MS (APCI), positive scan,m/z=579.1 (M+H).

Step B: Preparation of(S)—N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamidedi-hydrochloride

(S)—N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide(81.6 mg, 0.141 mmol) was taken up in 2 mL of 4:1 DCM/MeOH-4MHCl/dioxane (0.071 mL, 0.282 mmol) was added and the mixture stirred atambient temperature for one hour, then concentrated under reducedpressure and dried under vacuum for 16 hours to give 91.9 mgs (100%) ofthe HCl salt. [α]_(D)=−3.6° (c=1.0, CHCl₃).

Example 27(R)—N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamidedihydrochloride

Step A: Preparation of (R)-tert-butyl4-(2-hydroxyethyl)-2-methylpiperazine-1-carboxylate

Prepared according to Example 2, Step A, substituting (R)-tert-butyl2-methylpiperazine-1-carboxylate for 1-ethylpiperazine to give the finalproduct (70%).

Step B: Preparation of (R)-2-(3,4-dimethylpiperazin-1-yl)ethanol

Prepared according to Example 4, Step A, substituting (R)-tert-butyl4-(2-hydroxyethyl)-2-methylpiperazine-1-carboxylate for tert-Butyl6-(2-hydroxyethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate, to give thefinal product (81%).

Step C: Preparation of(R)—N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according Example 1, Step B, substitutingN-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide(Example 16, Steps A-G) for7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand substituting (R)-2-(3,4-dimethylpiperazin-1-yl)ethanol for2-morpholinoethanol to give the title compound (34%). MS (APCI),positive scan, m/z=579.1 (M+H).

Step D: Preparation of(R)—N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamidedi-hydrochloride:(R)—N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide(79.3 mg, 0.139 mmol) was taken up in 2 mL of 4:1 DCM/MeOH. 4MHCl/dioxane (0.069 mL, 0.278 mmol) was added and the mixture stirred atambient temperature for one hour, then concentrated under reducedpressure and dried under vacuum for 16 hours to give 89 mg (100%) of theHCl salt. [α]_(D)=+3.3° (c=1.0, CHCl₃).

Example 28(R)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

7-Fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Example 1, Step A), 0.300 g, 0.678 mmol),(R)-2-(3,4-dimethylpiperazin-1-yl)ethanol (0.536 g, 3.39 mmol), andpotassium t-butoxide (0.456 g, 4.07 mmol) were combined in t-butanol ina pressure tube. The tube was sealed and warmed to 95° C. for 16 hours,then allowed to cool to ambient temperature. The mixture was dilutedwith water and extracted with EtOAc. The combined organic extracts werewashed with 10% aqueous potassium carbonate, dried over sodium sulfateand concentrated under reduced pressure. Column chromatography (10%MeOH/DCM/0.5% NH₄OH) of the crude material followed by trituration withether gave 136 mg (33%) of the title compound. MS (APCI), positive scan,m/z=581.1 (M+H). [α]_(D)=−5.3° (c=1.0, CHCl₃).

Example 29(S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according Example 1, Step B, substituting7-fluoro-N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Example 8, Steps A-G) for7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol for 2-morpholinoethanol togive the title compound (50%). MS (APCI), positive scan, m/z=585.4(M+H).

Example 30(S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(1-((2-isopropylthiazol-4-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according Example 1, Step B, substituting7-fluoro-N-(1-((2-isopropylthiazol-4-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Example 12, Steps A-E) for7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol for 2-morpholinoethanol togive the title compound (22%). MS (APCI), positive scan, m/z=587.2(M+H).

Example 31(S)—N-(1-((6-tert-butylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of (6-tert-butylpyridin-2-yl)methanol

Prepared according to Example 16, Step B, substituting6-tert-butylpicolinaldehyde for 6-cyclopropylpicolinaldehyde, to givethe title compound (60%).

Step B: Preparation of 2-tert-butyl-6-(chloromethyl)pyridinehydrochloride

Prepared according to Preparation D, Step B, substituting(6-tert-butylpyridin-2-yl)methanol for 6-isopropylpyridin-2-yl)methanol,to give the title compound (100%).

Step C: Preparation of3-bromo-1-((6-tert-butylpyridin-2-yl)methyl)-4-nitro-1H-indazole

Prepared according to Preparation D, Step D, substituting2-tert-butyl-6-(chloromethyl)pyridine hydrochloride for2-(chloromethyl)-6-isopropylpyridine hydrochloride, to give the titlecompound (55%).

Step D: Preparation of1-((6-tert-butylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole

Prepared according to Preparation D, Step E, substituting3-bromo-1-((6-tert-butylpyridin-2-yl)methyl)-4-nitro-1H-indazole for3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole, to givethe title compound (64%).

Step E: Preparation of1-((6-tert-butylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine

Prepared according to Preparation D, Step F, substituting1-((6-tert-butylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole for1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole, togive the title compound (73%).

Step F: Preparation ofN-(1-((6-tert-butylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1, Step A, substituting1-((6-tert-butylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine for1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine, to givethe title compound (55%).

Step G: Preparation ofS)—N-(1-((6-tert-butylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according Example 1, Step B, substitutingN-(1-((6-tert-butylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamidefor7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol for 2-morpholinoethanol togive the title compound (54%). MS (APCI), positive scan, m/z=595.1(M+H).

Example 32(S)—N-(1-((6-cyclobutylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 2-bromo-6-cyclobutylpyridine

A round bottom flask was charged with dry THF (50 mL),2,6-dibromopyridine (3.00 g, 12.7 mmol), copper iodide (0.555 g, 2.91mmol) and PdCl₂(dppf):dichloromethane adduct (1.09 g, 1.33 mmol). Themixture was purged with argon for 10 minutes, and then cyclobutyl zincbromide (0.5 M in THF, 30.4 mL, 15.2 mmol) was added and the mixturestirred at ambient temperature for 2 hours. The mixture was quenchedwith saturated ammonium chloride solution and extracted with EtOAc. Thecombined organic extracts were dried over sodium sulfate andconcentrated under reduced pressure. Column chromatography (5% ethylacetate/hexane) afforded 1.48 g (55%) of the title compound as an orangeoil.

Step B: Preparation of 6-cyclobutylpicolinaldehyde

Prepared according to Example 16, Step A, substituting2-bromo-6-cyclobutylpyridine for 2-bromo-6-cyclopropylpyridine, to givethe title compound (52%).

Step C: Preparation of (6-cyclobutylpyridin-2-yl)methanol

Prepared according to Example 16, Step B, substituting6-cyclobutylpicolinaldehyde for 6-cyclopropylpicolinaldehyde, to givethe title compound (82%).

Step D: Preparation of 2-(chloromethyl)-6-cyclobutylpyridinehydrochloride

Prepared according to Preparation D, Step B, substituting(6-cyclobutylpyridin-2-yl)methanol for 6-isopropylpyridin-2-yl)methanol,to give the title compound (100%).

Step E: Preparation of3-bromo-1-((6-cyclobutylpyridin-2-yl)methyl)-4-nitro-1H-indazole

Prepared according to Preparation D, Step D, substituting2-(chloromethyl)-6-cyclobutylpyridine hydrochloride for2-(chloromethyl)-6-isopropylpyridine hydrochloride, to give the titlecompound (68%).

Step F: Preparation of1-((6-cyclobutylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole

Prepared according to Preparation D, Step E, substituting3-bromo-1-((6-cyclobutylpyridin-2-yl)methyl)-4-nitro-1H-indazole for3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole, to givethe title compound (72%).

Step G: Preparation of1-((6-cyclobutylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine

Prepared according to Preparation D, Step F, substituting1-((6-cyclobutylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole for1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole, togive the title compound (50%).

Step H: Preparation ofN-(1-((6-cyclobutylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1, Step A, substituting1-((6-cyclobutylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine for1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine, to givethe title compound (40%).

Step I: Preparation of(S)—N-(1-((6-cyclobutylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according Example 1, Step B, substitutingN-(1-((6-cyclobutylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamidefor7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol for 2-morpholinoethanol togive the title compound (29%). MS (APCI), positive scan, m/z=593.1(M+H).

Example 33(S)—N-(1-((6-cyclopentylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 2-bromo-6-cyclopentylpyridine

Prepared according to Example 32, Step A, substituting cyclopentyl zincbromide for cyclobutyl zinc bromide, to give the title compound (45%).

Step B: Preparation of (6-cyclopentylpyridin-2-yl)methanol

A flame dried flask was charged with dry THF (88 mL) and chilled to −78°C. To this was added n-BuLi (3.54 mL, 8.85 mmol, 2.5 M in hexanes),followed by the slow addition of a THF (10 mL) solution of2-bromo-6-cyclopentylpyridine (2.00 g, 8.85 mmol) over a 15 minuteperiod. The mixture was stirred at −78° C. for 15 minutes, and neat DMF(1.03 mL, 13.3 mmol) was added. The mixture was stirred for 15 minutesat −78° C., then quenched with saturated ammonium chloride solution andallowed to warm up to ambient temperature. The mixture was diluted withwater and extracted with EtOAc. The combined organic extracts were driedover sodium sulfate and concentrated under reduced pressure to give 1.6g of a brown oil. The crude material was then taken up in methanol (50mL), chilled to 0° C. and NaBH₄ (1.00 g, 26.5 mmol) was then added.After 10 minutes, the mixture was allowed to warm to ambient temperatureand stirred for 2 hours. The mixture was concentrated under reducedpressure, and the residue was taken up in saturated ammonium chloridesolution, extracted with EtOAc, extracts dried over sodium sulfate andconcentrated. Column Chromatography (100% ethyl acetate) of the crudematerial afforded 0.549 g (35%) of the title compound as an orange oil.

Step C: Preparation of 2-(chloromethyl)-6-cyclopentylpyridinehydrochloride

Prepared according to Preparation D, Step B, substituting(6-cyclopentylpyridin-2-yl)methanol for6-isopropylpyridin-2-yl)methanol, to give the title compound (100%).

Step D: Preparation of3-bromo-1-((6-cyclopentylpyridin-2-yl)methyl)-4-nitro-1H-indazole

Prepared according to Preparation D, Step D, substituting2-(chloromethyl)-6-cyclopentylpyridine hydrochloride for2-(chloromethyl)-6-isopropylpyridine hydrochloride, to give the titlecompound (69%).

Step E: Preparation of1-((6-cyclopentylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole

Prepared according to Preparation D, Step E, substituting3-bromo-1-((6-cyclopentylpyridin-2-yl)methyl)-4-nitro-1H-indazole for3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole, to givethe title compound (67%).

Step F: Preparation of1-((6-cyclopentylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine

1-((6-cyclopentylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole(0.470 g, 1.40 mmol) was dissolved in 14 mL of methanol. To thissolution was added 20% Pd(OH)₂ (0.470 g, 50% water content) and thereaction mixture was stirred under a hydrogen balloon for 2 hours. Thismixture was filtered through GF/F filter paper and the filtrate wasconcentrated to 0.340 g (79%) of the title compound.

Step G: Preparation of7-chloro-N-(1-((6-cyclopentylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1, Step A, substituting ethyl7-chloroimidazo[1,2-a]pyridine-3-carboxylate for ethyl7-fluoroimidazo[1,2-a]pyridine-3-carboxylate and1-((6-cyclopentylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine for1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine to givethe title compound (56%).

Step H: Preparation of(S)—N-(1-((6-cyclopentylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 7, Step F, substituting7-chloro-N-(1-((6-cyclopentylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamidefor7-chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol for2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)ethanol to give the titlecompound (17%). MS (APCI), positive scan, m/z=607.1 (M+H).

Example 34(S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(1-((4,6-dimethylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of (4,6-dimethylpyridin-2-yl)methanol

Prepared according to Example 16, Step B, substituting4,6-dimethylpicolinaldehyde for 6-cyclopropylpicolinaldehyde, to givethe title compound (71%).

Step B: Preparation of 2-(chloromethyl)-4,6-dimethylpyridinehydrochloride

Prepared according to Preparation D, Step B, substituting(4,6-dimethylpyridin-2-yl)methanol for 6-isopropylpyridin-2-yl)methanol,to give the title compound (100%).

Step C: 3-bromo-1-((4,6-dimethylpyridin-2-yl)methyl)-4-nitro-1H-indazole

Prepared according to Preparation D, Step D, substituting2-(chloromethyl)-4,6-dimethylpyridine hydrochloride for2-(chloromethyl)-6-isopropylpyridine hydrochloride, to give the titlecompound (100%).

Step D: Preparation of1-((4,6-dimethylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole

Prepared according to Preparation D, Step E, substituting3-bromo-1-((4,6-dimethylpyridin-2-yl)methyl)-4-nitro-1H-indazole for3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole, to givethe title compound (59%).

Step E: Preparation of1-((4,6-dimethylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine

Prepared according to Example 33, Step F, substituting1-((4,6-dimethylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole for1-((6-cyclopentylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole, togive the title compound (88%).

Step F: Preparation of7-chloro-N-(1-((4,6-dimethylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1, Step A, substituting ethyl7-chloroimidazo[1,2-a]pyridine-3-carboxylate for ethyl7-fluoroimidazo[1,2-a]pyridine-3-carboxylate and1-((4,6-dimethylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine for1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine to givethe title compound (54%).

Step G: Preparation of(S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(1-((4,6-dimethylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 7, Step F, substituting7-chloro-N-(1-((4,6-dimethylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamidefor7-chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol for2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)ethanol to give the titlecompound (42%). MS (APCI), positive scan, m/z=567.1 (M+H).

Example 35(S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 2-(chloromethyl)-6-methylpyridine hydrochloride

Prepared according to Preparation D, Step B, substituting(6-methylpyridin-2-yl)methanol for 6-isopropylpyridin-2-yl)methanol, togive the title compound (100%).

Step B: Preparation of3-bromo-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole

Prepared according to Preparation D, Step D, substituting2-(chloromethyl)-6-methylpyridine hydrochloride for2-(chloromethyl)-6-isopropylpyridine hydrochloride, to give the titlecompound (56%).

Step C: Preparation of3-methyl-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole

Prepared according to Preparation D, Step E, substituting3-bromo-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole for3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole, to givethe title compound (67%).

Step D: Preparation of3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine

Prepared according to Example 33, Step F, substituting3-methyl-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole for1-((6-cyclopentylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole, togive the title compound (84%).

Step E: Preparation of7-chloro-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1, Step A, substituting ethyl7-chloroimidazo[1,2-a]pyridine-3-carboxylate for ethyl7-fluoroimidazo[1,2-a]pyridine-3-carboxylate and3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine for1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine to givethe title compound (38%).

Step F: Preparation of(S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 7, Step F, substituting7-chloro-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamidefor7-chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol for2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)ethanol to give the titlecompound (11%). MS (APCI), positive scan, m/z=553.1 (M+H).

Example 36(S)-7-(2-(3,4-dimethylpiperazin--yl)ethoxy)-N-(1-((6-ethylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of ethyl 6-vinylpicolinate

Prepared according to Preparation C, Step E, substituting potassiumtrifluoro(vinyl)borate for potassium trifluoro(prop-1-en-2-yl)borate togive the title compound (99%).

Step B: Preparation of ethyl 6-ethylpicolinate

Ethyl 6-vinylpicolinate (4.70 g, 26.5 mmol) was dissolved in 100 mL ofethanol. To this was added 20% Pd(OH)₂ on carbon (1 g, 50% water) andthe mixture was stirred under a hydrogen balloon for 2 hours. Themixture was purged with nitrogen, filtered through GF/F filter paper,and the filtrate concentrated under reduced pressure to give 4.5 g (95%)of the title compound.

Step C: Preparation of (6-ethylpyridin-2-yl)methanol

Prepared according to Preparation D, Step A, substituting ethyl6-ethylpicolinate for Ethyl 6-isopropylpicolinate, to give the titlecompound (41%).

Step D: Preparation of 2-(chloromethyl)-6-ethylpyridine hydrochloride

Prepared according to Preparation D, Step B, substituting(6-ethylpyridin-2-yl)methanol for 6-isopropylpyridin-2-yl)methanol, togive the title compound (100%).

Step E: Preparation of3-bromo-1-((6-ethylpyridin-2-yl)methyl)-4-nitro-1H-indazole

Prepared according to Preparation D, Step D, substituting2-(chloromethyl)-6-ethylpyridine hydrochloride for2-(chloromethyl)-6-isopropylpyridine hydrochloride, to give the titlecompound (72%).

Step F: Preparation of1-((6-ethylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole

Prepared according to Preparation D, Step E, substituting3-bromo-1-((6-ethylpyridin-2-yl)methyl)-4-nitro-1H-indazole for3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole, to givethe title compound (70%).

Step G: Preparation of1-((6-ethylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine

Prepared according to Example 33, Step F, substituting1-((6-ethylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole for1-((6-cyclopentylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole, togive the title compound (93%).

Step H: Preparation of7-chloro-N-(1-((6-ethylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1, Step A, substituting ethyl7-chloroimidazo[1,2-a]pyridine-3-carboxylate for ethyl7-fluoroimidazo[1,2-a]pyridine-3-carboxylate and1-((6-ethylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine for1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine to givethe title compound (45%).

Step I: Preparation of(S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(1-((6-ethylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 7, Step F, substituting7-chloro-N-(1-((6-ethylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamidefor7-chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol for2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)ethanol to give the titlecompound (27%). MS (APCI), positive scan, m/z=567.1 (M+H).

Example 37N-(1-((6-sec-butylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-((S)-3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 33, Steps A through H,starting with sec-butyl zinc bromide instead of cyclopentyl zinc bromidein Step A. MS (APCI), positive scan, m/z=595.1 (M+H).

Example 38(S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(3-methyl-1-((5-propylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 33, Steps B through H, using2-bromo-5-propylpyridine instead of 2-bromo-6-cyclopentylpyridine inStep B. MS (APCI), positive scan, m/z=581.1 (M+H).

Example 39(S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(1-((5-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 5-(prop-1-en-2-yl)picolinaldehyde

Prepared according to Preparation C, Step E, substituting5-bromopicolinaldehyde for ethyl 6-chloropicolinate to give the titlecompound (77%).

Step B: Preparation of (5-isopropylpyridin-2-yl)methanol

5-(prop-1-en-2-yl)picolinaldehyde (0.600 g, 4.08 mmol) was dissolved inmethanol (15 mL). To this was added Pd(OH)₂ (0.600 mgs, 20% catalyst oncarbon, 50% water by weight) and the mixture was hydrogenated under aballoon of hydrogen for 2 hours. The mixture was then filtered throughGF/F filter paper and the filtrate was concentrated under reducedpressure to give the title compound (84%).

Step C: Preparation of(S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(1-((5-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Example 39 was prepared according to Example 33, Steps C through H,using (5-isopropylpyridin-2-yl)methanol instead of(6-cyclopentylpyridin-2-yl)methanol in Step C. MS (APCI), positive scan,m/z=581.1 (M+H).

Example 40(S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(1-((6-isobutylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 33, Steps A through H, usingisobutyl zinc bromide instead of cyclopentyl zinc bromide in Step A. MS(APCI), positive scan, m/z=595.2 (M+H).

Example 41(S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(1-((5-fluoro-6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 6-bromo-5-fluoropicolinic acid

2-Bromo-3-fluoro-6-methylpyridine (3.60 g, 18.9 mmol) was dissolved in10 mL of pyridine in pressure tube. To this was added 50 mL of water,and the mixture was warmed to 85° C. Potassium permanganate (5.99 g,37.9 mmol) was added, the tube was capped, and the mixture was stirredat 85° C. for 48 hours. The mixture was filtered through GF/F filterpaper, and the filtrate was concentrated to about half volume underreduced pressure. The remaining material was acidified to pH 4 with 1Maqueous HCl and extracted with EtOAc. The combined organic extracts weredried over sodium sulfate and concentrated under reduced pressure togive 0.70 g of the title compound (17%).

Step B: Preparation of1-((5-fluoro-6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole

Prepared according to Preparation C, Steps D through F and PreparationD, Steps B, D and E, starting with 6-bromo-5-fluoropicolinic acidinstead of 6-chloropicolinic acid in Preparation C, Step D, to give thetitle compound.

Step C: Preparation of1-((5-fluoro-6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine

Prepared according to Example 33, Step F, substituting1-((5-fluoro-6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazolefor 1-((6-cyclopentylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole,to give the title compound (87%).

Step D: Preparation of(S)-4-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)pyridin-2-amine

4-Chloropyridin-2-amine (0.500 g, 3.89 mmol),(S)-2-(3,4-dimethylpiperazin-1-yl)ethanol (1.23 g, 7.78 mmol), andcrushed potassium hydroxide (0.546 g, 9.72 mmol) were combined in 8 mLof DMSO in a pressure tube and heated to 95° C. for 16 hours. Themixture was then diluted with water (100 mL), extracted 2 times withEtOAc, extracts washed with brine, dried and concentrated under reducedpressure. Column chromatography (5% MeOH/DCM) afforded 0.484 g (50%) ofthe title compound.

Step E: Preparation of (S)-ethyl7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate

Prepared according to Preparation C, Step C, substituting(S)-4-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)pyridin-2-amine for4-fluoropyridin-2-amine, to give the title compound (25%).

Step F: Preparation of(S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(1-((5-fluoro-6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1, Step A, substituting (S)-ethyl7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylatefor ethyl 7-fluoroimidazo[1,2-a]pyridine-3-carboxylate and1-((5-fluoro-6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-aminefor 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine, togive the title compound (46%). MS (APCI), positive scan, m/z=599.2(M+H).

Example 42(S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(3-methyl-1-(2-(6-methylpyridin-2-yl)ethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of3-bromo-1-(2-(6-methylpyridin-2-yl)ethyl)-4-nitro-1H-indazole

Prepared according to Preparation D, Step D, substituting2-(2-bromoethyl)-6-methylpyridine hydrobromide for2-(chloromethyl)-6-isopropylpyridine hydrochloride, to give the titlecompound (31%).

Step B: Preparation of3-methyl-1-(2-(6-methylpyridin-2-yl)ethyl)-4-nitro-1H-indazole

Prepared according to Preparation D, Step E, substituting3-bromo-1-(2-(6-methylpyridin-2-yl)ethyl)-4-nitro-1H-indazole for),3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole, to givethe title compound (83%).

Step C: Preparation of3-methyl-1-(2-(6-methylpyridin-2-yl)ethyl)-1H-indazol-4-amine

Prepared according to Example 33, Step F, substituting3-methyl-1-(2-(6-methylpyridin-2-yl)ethyl)-4-nitro-1H-indazole for1-((6-cyclopentylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole, togive the title compound (68%).

Step D: Preparation of7-chloro-N-(3-methyl-1-(2-(6-methylpyridin-2-yl)ethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1, Step A, substituting ethyl7-chloroimidazo[1,2-a]pyridine-3-carboxylate for ethyl7-fluoroimidazo[1,2-a]pyridine-3-carboxylate and3-methyl-1-(2-(6-methylpyridin-2-yl)ethyl)-1H-indazol-4-amine for1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine to givethe title compound (100%).

Step E: Preparation of(S)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)-N-(3-methyl-1-(2-(6-methylpyridin-2-yl)ethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 7, Step F, substituting7-chloro-N-(3-methyl-1-(2-(6-methylpyridin-2-yl)ethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamidefor7-chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol for2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)ethanol to give the titlecompound (6%). MS (APCI), positive scan, m/z=567.1 (M+H).

Example 43(S)—N-(1-((6-cyclopropylpyridin-2-yl)methyl)-5-fluoro-3-methyl-1H-indazol-4-yl)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 6-fluoro-2-methyl-3-nitrobenzoic acid

2-Fluoro-6-methylbenzoic acid (40 g, 0.26 mol) was dissolved in 320 mLof sulfuric acid and chilled to −15° C. To this was added 14 mL offuming nitric acid in 60 mL of sulfuric acid over a 10 minute period.Once the addition was complete, the mixture was stirred at 0° C. for 1hour, then poured into ice water, and stirred. The resulting solids werecollected and then dissolved in EtOAc, which was washed with water,dried over sodium sulfate and concentrated to 50 g (97%) of the titlecompound.

Step B: Preparation of methyl 6-fluoro-2-methyl-3-nitrobenzoate

To a mixture of 6-fluoro-2-methyl-3-nitrobenzoic acid (21.2 g, 0.107mol), powdered potassium carbonate (36.8, 0.266 mol) in DMF (200 mL) wasadded methyl iodide (37.8 g, 0.266 mol). The mixture was stirred atambient temperature for 16 hours, then diluted with water and extractedwith EtOAc. The combined organic extracts were washed with brine, driedover sodium sulfate and concentrated under reduced pressure. Columnchromatography (20% ethyl acetate/hexane) afforded 12.6 g (56%) of thetitle compound.

Step C: Preparation of methyl 3-amino-6-fluoro-2-methylbenzoate

Prepared according to Example 33, Step F, substituting methyl6-fluoro-2-methyl-3-nitrobenzoate for1-((6-cyclopentylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole, togive the title compound (95%).

Step D: Preparation of methyl-5-fluoro-1H-indazole-4-carboxylate

Methyl 3-amino-6-fluoro-2-methylbenzoate (7.50 g, 0.041 mol) wasdissolved in 150 mL of acetic acid. To this was added acetic anhydride(14.6 g, 0.143 mol) and the mixture was warmed to 75° C. Sodium nitrite(11.3 g, 0.164 mol) was added in portions to the reaction mixture(evolution of an gas observed). The mixture was stirred at 75° C. for 16hours, then allowed to cool to ambient temperature, and then poured intocold 10% aqueous potassium carbonate solution. This material wasextracted twice with EtOAc, the extracts dried over sodium sulfate andconcentrated under reduced pressure. Column chromatography (1:1EtOAc/Hexanes) afforded 0.48 g of methyl1-acetyl-5-fluoro-1H-indazole-4-carboxylate. The crude material was thenadded to 5 mL of 4M HCl/dioxane and 15 mL of methanol in a pressure tubeand heated to 60° C. for 2 hours. The mixture was concentrated underreduced pressure and the resulting solids were taken up in 10% aqueouspotassium carbonate/EtOAc. The organic layer was isolated, dried oversodium sulfate and concentrated under reduced pressure to give 0.483 g(5%) of the title compound.

Step E: Preparation of methyl 3-bromo-5-fluoro-1H-indazole-4-carboxylate

To a solution of methyl-5-fluoro-1H-indazole-4-carboxylate (0.475 g,2.45 mmol) in 25 mL of DMF was added N-bromosuccinimide (0.566 g, 3.18mmol). This mixture was stirred at ambient temperature for one hour,then quenched with water. This mixture was extracted with EtOAc, and thecombined organic extracts washed with brine, dried over sodium sulfateand concentrated under reduced pressure. Column chromatography (1:1EtOAc/Hexane) afforded 0.459 g (69%) of the title compound.

Step F: Preparation of methyl3-bromo-1-((6-cyclopropylpyridin-2-yl)methyl)-5-fluoro-1H-indazole-4-carboxylate

Prepared according to Preparation D, Step D, substituting methyl3-bromo-5-fluoro-1H-indazole-4-carboxylate for3-bromo-4-nitro-1H-indazole and 2-(chloromethyl)-6-cyclopropylpyridinehydrochloride for 2-(chloromethyl)-6-isopropylpyridine hydrochloride, togive the title compound (77%).

Step G: Preparation of methyl1-((6-cyclopropylpyridin-2-yl)methyl)-5-fluoro-3-methyl-1H-indazole-4-carboxylate

Prepared according to Preparation D, Step E, substituting methyl3-bromo-1-((6-cyclopropylpyridin-2-yl)methyl)-5-fluoro-1H-indazole-4-carboxylatefor 3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole, togive the title compound (73%).

Step H: Preparation of1-((6-cyclopropylpyridin-2-yl)methyl)-5-fluoro-3-methyl-1H-indazole-4-carboxylicacid

Methyl1-((6-cyclopropylpyridin-2-yl)methyl)-5-fluoro-3-methyl-1H-indazole-4-carboxylate(0.310 g, 0.913 mmol) was subjected to 1M aqueous lithium hydroxide(1.83 mL, 1.83 mmol) in 10 mL of THF for 16 hours at reflux. The mixturewas then diluted with 1M aqueous HCl (to pH 4), and extracted twice withEtOAc. The combined organic extracts were dried over sodium sulfate andconcentrated to give 0.206 g (69%) of the title compound.

Step I: Preparation of1-((6-cyclopropylpyridin-2-yl)methyl)-5-fluoro-3-methyl-1H-indazol-4-amine

1-((6-Cyclopropylpyridin-2-yl)methyl)-5-fluoro-3-methyl-1H-indazole-4-carboxylicacid (0.205 g, 0.630 mmol) was dissolved in 6 mL of DMF. To this wasadded diphenylphosphoryl azide (0.260 g, 0.945 mmol) and TEA (0.263 mL,1.89 mmol) and the mixture was stirred at ambient temperature for 1.5hours. Water (5 mL) was added and the mixture was warmed to 80° C. for 2hours, then allowed to stir at ambient temperature for 16 hours. Thereaction mixture was diluted with water and extracted twice with EtOAc.The combined organic extracts washed with brine, dried over sodiumsulfate, and concentrated under reduced pressure. Column chromatography(1:1 EtOAc:Hexanes) of the crude material afforded 0.107 g (57%) of thetitle compound.

Step J: Preparation ofN-(1-((6-cyclopropylpyridin-2-yl)methyl)-5-fluoro-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1, Step A, substituting1-((6-cyclopropylpyridin-2-yl)methyl)-5-fluoro-3-methyl-1H-indazol-4-aminefor 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine, togive the title compound (6.5%).

Step K: Preparation of(S)—N-(1-((6-cyclopropylpyridin-2-yl)methyl)-5-fluoro-3-methyl-1H-indazol-4-yl)-7-(2-(3,4-dimethylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according Example 1, Step B, substitutingN-(1-((6-cyclopropylpyridin-2-yl)methyl)-5-fluoro-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamidefor7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand substituting (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol for2-morpholinoethanol to give the title compound (20%). MS (APCI),positive scan, m/z=597.1 (M+H).

Example 447-(2-(4-isopropylpiperazazin-1-yl)ethoxy)-N-(3-methyl-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Step A: Preparation of ethyl7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate

Potassium (E)-2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (Preparation B;41.32 g, 219.0 mmol) was suspended (through vigorous magnetic stirring)in anhydrous ether (0.3M, 365 mL) and 6 N sulfuric acid (18.25 ml, 109.5mmol) was added. More water (about 100 mL) was added to aid in phaseseparation. When the pH of the bottom (aqueous) layer dropped below 3,the ether layer was separated. The aqueous layer was further extractedwith ether (400 mL). The combined ether phases were dried over sodiumsulfate and magnesium sulfate for 10 minutes. The solution was filteredand concentrated under reduced pressure, with the temperature of thewater bath not exceeding 20° C. An oil was obtained, which solidifiedupon drying under high vacuum overnight. The solid was dissolved inabsolute EtOH (0.3M, 360 mL),4-(2-(4-isopropylpiperazin-1-yl)ethoxy)pyridin-2-amine (28.95 g, 109.5mmol) was added, and the mixture was heated under nitrogen at 65° C. for18 hours. After allowing the mixture to cool, the resulting suspensionwas evaporated to dryness. The resulting solids were shaken with THF andcollected by filtration, then dried under vacuum. The crude material(isolated as the HCl salt) was mixed with water (400 mL) and ethanol(200 mL). Sodium bicarbonate (20 g) was added and stirred overnight. Thesuspension was evaporated to dryness under vacuum. The solids wereshaken in EtOAc/THF and isolated by filtration. The solids were thenwashed with a large volume of ethyl acetate and THF under gravity. Thefiltrate was further dried with sodium sulfate and magnesium sulfate,filtered and evaporated to an amber gum. This material was trituratedwith 2:1 ether-hexanes, and the resulting solids were collected byfiltration to afford ethyl7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate(23.46 g, 59% yield).

Step B: Preparation of lithium7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate

To ethyl7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate(5.68 g, 15.8 mmol) in water (30 mL) was added lithium hydroxide hydrate(0.67 g, 16.0 mmol). The reaction was heated to 95° C. for 4 hours. Thereaction was cooled to ambient temperature and hydrogen chloride (0.0394mL, 4M in dioxane) was added to the reaction mixture, which was stirredfor 10 minutes. Water was removed under vacuum for overnight to give thetitle compound (5.43 g).

Step C: Preparation of 2-(chloromethyl)-5-(trifluoromethyl)pyridinehydrochloride

Prepared according to Preparation D, Step B, substituting(5-(trifluoromethyl)pyridin-2-yl)methanol forisopropylpyridin-2-yl)methanol, to give the title compound (100%).

Step D: Preparation of3-bromo-4-nitro-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazole

Prepared according to Preparation D, Step D, substituting2-(chloromethyl)-5-(trifluoromethyl)pyridine hydrochloride for2-(chloromethyl)-6-isopropylpyridine hydrochloride, to give the titlecompound (59%).

Step E: Preparation of3-methyl-4-nitro-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazole

Prepared according to Preparation D, Step E, substituting3-bromo-4-nitro-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazolefor 3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole, togive the title compound (42%).

Step F: Preparation of3-methyl-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-amine

Prepared according to Preparation D, Step F, substituting3-methyl-4-nitro-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazolefor 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole, togive the title compound (91%).

Step G: Preparation of7-(2-(4-isopropylpiperazin-1-yl)ethoxy)-N-(3-methyl-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Lithium7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate(0.746 g, 2.204 mmol) was dissolved in 16 mL of dry NMP. To this wasadded 2,4,6-trichlorobenzoyl chloride (0.538 g, 2.20 mmol) and thismixture was stirred at ambient temperature for 30 minutes.3-Methyl-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-amine(0.500 g, 1.63 mmol) was added and the mixture was warmed to 90° C. for16 hours, then allowed to cool to ambient temperature. Water (50 mL) wasadded and the mixture extracted with EtOAc. The extracts were thenwashed with 10% aqueous potassium carbonate solution and brine, driedover sodium sulfate, and concentrated under reduced pressure. Columnchromatography (7% MeOH/DCM/0.5% NH₄OH) afforded 0.112 g (11%) of thefinal compound. MS (APCI), positive scan, m/z=622.2 (M+H).

Example 457-(2-(4-isopropylpiperazin-1-yl)ethoxy)-N-(3-methyl-1-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 2-(chloromethyl)-6-(trifluoromethyl)pyridinehydrochloride

Prepared according to Preparation D, Step B, substituting(6-(trifluoromethyl)pyridin-2-yl)methanol forisopropylpyridin-2-yl)methanol to give the title compound (100%).

Step B: Preparation of3-bromo-4-nitro-1-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazole

Prepared according to Preparation D, Step D, substituting2-(chloromethyl)-6-(trifluoromethyl)pyridine hydrochloride for2-(chloromethyl)-6-isopropylpyridine hydrochloride, to give the titlecompound (81%).

Step C: Preparation of3-methyl-4-nitro-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazole

Prepared according to Preparation D, Step E, substituting3-bromo-4-nitro-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazolefor 3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole, togive the title compound (42%).

Step D: Preparation of3-methyl-1-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-amine

Prepared according to Preparation D, Step F, substituting3-methyl-4-nitro-1-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazolefor 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-H-indazole togive the title compound.

Step E: Preparation of 7-fluoroimidazo[1,2-a]pyridine-3-carboxylic acid

Ethyl 7-fluoroimidazo[1,2-a]pyridine-3-carboxylate (8 g; 44.4 mmol) wasmixed with tetrahydrofuran (225 mL), ethanol (110 mL) and water (55 mL).Lithium hydroxide monohydrate (0.962 g; 22.9 mmol) was added. Themixture was stirred at ambient temperature overnight. The mixtureconcentrated under reduced pressure to remove tetrahydrofuran andethanol. 2 N hydrochloric acid was added to aqueous mixture to adjust topH 3. A white precipitate formed and was filtered off with drying underhigh vacuum overnight to give7-fluoroimidazo[1,2-a]pyridine-3-carboxylic acid as a white solid (6.3g).

Step F: Preparation of7-fluoro-N-(3-methyl-1-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 44, Step G, substituting7-fluoroimidazo[1,2-a]pyridine-3-carboxylic acid for lithium7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylateand substituting3-methyl-1-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-aminefor3-methyl-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-amine,to give the title compound (20%).

Step G: Preparation of7-(2-(4-isoproplpiperazin-1-yl)ethoxy)-N-(3-methyl-1-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1, Step B, substituting7-fluoro-N-(3-methyl-1-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamidefor7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand 2-(4-isopropylpiperazin-1-yl)ethanol for 2-morpholinoethanol, togive the final compound (41%). MS (APCI), negative scan, m/z=620.4(M−H).

Example 46(S)—N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of (S)-benzyl4-(2-hydroxyethyl)-2-methylpiperazine-1-carboxylate

Prepared according to Example 2, Step A, substituting (S)-benzyl2-methylpiperazine-1-carboxylate for 1-ethylpiperazine and sodiumbicarbonate for potassium carbonate to give the title compound (61%).

Step B: Preparation of (S)-2-(3-methylpiperazin-1-yl)ethanol

Prepared according to Example 33, Step F, substituting (S)-benzyl4-(2-hydroxyethyl)-2-methylpiperazine-1-carboxylate for1-((6-cyclopentylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole, togive the title compound (77%).

Step C: Preparation of(S)—N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(3-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 7, Step F, substituting(S)-2-(3-methylpiperazin-1-yl)ethanol for2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)ethanol, to give the finalcompound (19%). MS (APCI), positive scan, m/z=567.1 (M+H).

Example 47N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1, Step B, substitutingN-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamidefor7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand 2-(4-methylpiperazin-1-yl)ethanol for 2-morpholinoethanol, to givethe final product (45%). MS (APCI), positive scan, m/z=565.3 (M+H).

Example 48N-(1-((1-isopropyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamidebis hydrochloride

Step A: Preparation of (1-Isopropyl-1H-pyrazol-3-yl)methanol

Commercially available ethyl 1-isopropyl-1H-pyrazole-3-carboxylate wasdissolved in diethyl ether, the solution was cooled to 0° C., and a 1Mlithium aluminum solution in tetrahydrofuran was added. After stirringfor 3 hours, the reaction mixture was poured into a cold 30% aqueousRochelle's salt solution and was allowed to stir for one hour. Theresulting mixture was extracted twice with diethyl ether. The combinedorganic extracts were washed with 10% aqueous potassium carbonatesolution and brine, dried over sodium sulfate, and concentrated underreduced pressure to yield the desired compound (54% yield).

Step B: Preparation of 3-(chloromethyl)-1-isopropyl-1H-pyrazolehydrochloride

(1-Isopropyl-1H-pyrazol-3-yl)methanol was dissolved into dichloromethaneand SOCl₂ (2 equivalents) was added. The resulting mixture was allowedto stir overnight, then concentrated under vacuum to yield the desiredcompound (quantitative yield).

Step C: Preparation of3-bromo-1-((1-isopropylpyrazole-3-yl)methyl)-4-nitro-1H-indazole

Prepared according to Example 1, Step J, substituting3-(chloromethyl)-1-isopropyl-1H-pyrazole Hydrochloride for2-(chloromethyl)-6-isopropylpyridine hydrochloride to yield the desiredcompound (75% yield).

Step D: Preparation of3-methyl-1-((1-isopropylpyrazole-3-yl)methyl)-4-nitro-1H-indazole

Prepared according to Example 1, Step K, substituting3-Bromo-1-((1-isopropylpyrazole-3-yl)methyl)-4-nitro-1H-indazole for3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole to yieldthe desired compound (56%).

Step E: Preparation of3-methyl-1-((1-isopropylpyrazole-3-yl)methyl)-4-amino-1H-indazole

Prepared according to Example 1, Step L, substituting3-methyl-1-((1-isopropylpyrazole-3-yl)methyl)-4-nitro-1H-indazole for3-methyl-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole toyield the desired compound (77%).

Step F: Preparation of7-chloro-N-(1-((1-isopropyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

3-Methyl-1-((1-isopropylpyrazole-3-yl)methyl)-4-amino-1H-indazole (1equivalent) and ethyl 7-chloroimidazo[1,2-a]pyridine-3-carboxylate(Example 7 step D; 1 equivalent) were dissolved in dry THF (0.2 M) andthe resulting solution was cooled to 0° C. Lithiumbis(trimethylsilyl)amide (2.3 equivalents) was slowly added and theresulting mixture was allowed to warm to ambient temperature overnight.THF was removed under vacuum and the remaining material was partitionedbetween water and ethyl acetate. The bottom aqueous layer was extractedtwice with ethyl acetate. The combined organic extracts were combined,dried over sodium sulfate, filtered and \ concentrated to give desiredcompound (52% yield).

Step G: Preparation ofN-(1-((1-isopropyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamidebis hydrochloride

Prepared according to Example 7, Step F, substituting7-chloro-N-(1-((1-isopropyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamidefor7-chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand 2-(4-methylpiperazin-1-yl)ethanol for2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)ethanol. The HCl salt wasprepared by subjecting the compound to 4M HCl/ether (20 equivalents) inmethanol and concentrating under reduced pressure to give the bis-HClsalt (45%). MS (APCI), positive scan, m/z=556.3 (M+H).

Example 49N-(1-((1-isopropyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 48, Step G, substituting2-(4-isopropylpiperazin-1-yl)ethanol for2-(4-methylpiperazin-1-yl)ethanol, to give the final product (17%). MS(APCI), positive scan, m/z=584.3 (M+H).

Example 50N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(6-methylpyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamidedi-hydrochloride

Step A: Preparation of methyl7-bromoimidazo[1,2-a]pyridine-3-carboxylate

7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (4.93 g, 20.5 mmol) wasdissolved in 80 mL of dry dichloromethane. To this solution was addedoxalyl chloride (20.5 mL, 40.9 mmol, 2M in dichloromethane) followed bya few drops of DMF. The mixture was stirred at ambient temperature for16 hours, then concentrated under reduced pressure. The resultingmaterial was taken up in 100 mL of methanol and stirred at ambienttemperature for 6 hours, then concentrated under reduced pressure. Theresulting material was suspended in saturated aqueous sodiumbicarbonate, extracted with dichloromethane and EtOAc. The organics werecombined, dried over sodium sulfate and concentrated under reducedpressure to give 4.63 g (89%) of the title compound.

Step B: Preparation of7-bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 1, Step A, substituting3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine for1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine andmethyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate for ethyl7-fluoroimidazo[1,2-a]pyridine-3-carboxylate, to give the title compound(62%).

Step C: Preparation ofN-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(6-methylpyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamidedi-hydrochloride

7-Bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(0.0486 g, 0.102 mmol) was dissolved in 2 mL of 1:1 DME:DMF. To this wasadded 6-methylpyridin-3-ylboronic acid (0.0210 g, 0.153 mmol),Pd(dppf)Cl₂ (5 mol %), and 2M aqueous sodium carbonate (153 μL, 0.306mmol). Nitrogen was bubbled through the mixture for 5 minutes and themixture was then heated to 90° C. for 16 hours. The reaction mixture wasdiluted with EtOAc and the resulting precipitate was removed byfiltration. The filtrate was washed with water and brine, dried oversodium sulfate and concentrated under reduced pressure. Reverse phasechromatography of the crude material, followed by treatment with 4MHCl/dioxane gave the final product. MS (APCI), positive scan, m/z=488.2(M+H).

Example 51N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridine-3-carboxamidehydrochloride

7-Bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Example 50, Steps A-B; 0.0815 g, 0.171 mmol) was dissolved in 2 mL of1:1 (DME:DMF). To this was added tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(0.0795 g, 0.257 mmol), Pd(dppf)Cl₂ (5 mol %), and 2M aqueous sodiumcarbonate (256 μL, 0.513 mmol). Nitrogen was bubbled through thesolution for 5 minutes and the reaction mixture was then heated to 90°C. for 16 hours. The reaction mixture was then diluted with EtOAc andthe precipitate formed was filtered and the filtrate was washed withwater and brine, dried over sodium sulfate and concentrated underreduced pressure. The crude material was purified by reverse phasechromatography to provided tert-butyl4-(3-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate,which was treated 4M HCl/dioxane to give the title product. MS (APCI),positive scan, m/z=478.2 (M+H).

Example 52N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(piperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxamidetri-hydrochloride

tert-Butyl4-(3-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Example 51; 0.037 g, 0.064 mmol) was dissolved in 6 mLof methanol and 1.3 mL of 6N HCl in isopropyl alcohol. 10% Pd/C (0.075g) was added and the mixture hydrogenated under a balloon of hydrogenfor 2 hours. Celite was added and the mixture was then filtered throughGF/F filter paper and the filtrate concentrated under reduced pressure.The crude material was purified by reverse phase chromatography,followed by treatment of the isolated material with 4M HCl/dioxane toprovide the title compound (17% yield). MS (APCI), positive scan,m/z=480.3 (M+H).

Example 537-fluoro-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

7-Fluoroimidazo[1,2-a]pyridine-3-carboxylic acid (0.081 g, 0.449 mmol)was dissolved in thionyl chloride (2 mL). To this was added a few dropsof DMF and the mixture stirred at ambient temperature for 1 hour. Themixture was concentrated under reduced pressure and the resulting solidwas dissolved in 3 mL of 1:2 DCM:DMF. To this was added3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (0.114 g,0.451 mmol) followed by diisopropylethylamine (235 μL, 1.35 mmol). Thismixture was stirred at ambient temperature for 2 hours, then dilutedwith water (22 mL), forming a beige precipitate with stirring forseveral hours. The solids were collected to give 0.100 g (54%) of thetitle compound. MS (APCI), positive scan, m/z=415.2 (M+H).

Example 54N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(pyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxamidedihydrochloride

7-Fluoro-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Example 53; 0.0144 g, 0.0347 mmol) was suspended in n-butanol (0.2 mL).To this was added pyrrolidine (7.25 μL, 0.0869 mmol) and the mixture washeated to 120° C. for 12 hours. The mixture was concentrated underreduced pressure and the resulting material was taken up in THF andconcentrated three times to give a brown solid. This material was takenup in dichloromethane, washed with water and brine, dried over sodiumsulfate and concentrated under reduced pressure (0.0127 g, 79%). Theresulting material was treated with 2M HCl in diethyl ether to provideN-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(pyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxamidedihydrochloride. MS (APCI), positive scan, m/z=466.3 (M+H).

Example 55N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(pyrrolidin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamidedihydrochloride

Prepared according to Example 1, Step B, substituting7-fluoro-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Example 53) for7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand 2-(pyrrolidin-1-yl)ethanol for 2-morpholinoethanol. Purification ofthe crude material by reverse phase chromatography gave 71 mg (41%) ofthe product, which was treated with 2M HCl/ether to give thedihydrochloride salt. MS (APCI), positive scan, m/z=510.0 (M+H).

Example 56 tert-Butyl4-(2-(3-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridin-7-yloxy)ethyl)piperazine-1-carboxylate

To a 0.4 M solution of potassium tert-butoxide (0.068 g, 0.606 mmol) inTHF cooled in an ice-water bath was added tert-butyl4-(2-hydroxyethyl)piperazine-1-carboxylate 0.278 g, 1.21 mmol). Thereaction was stirred for 10 minutes before adding7-fluoro-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Example 53; 0.100 g 0.241 mmol) in 2 mL of NMP. The reaction was warmedto ambient temperature and stirred for 1 hour, then heated to 60° C. andstirred for 12 hours. THF was removed by rotary evaporation and themixture was heated to 120° C. for 5 hours. Another equivalent ofpotassium t-butoxide was added and the mixture was heated for another 3hours. The reaction was quenched with water and extracted with EtOAc.The extracts were dried over sodium sulfate and concentrated underreduced pressure. Purification by preparative thin layer chromatographyand reverse phase chromatography gave the title compound. MS (APCI),positive scan, m/z=625.0 (M+H).

Example 577-(2-hydroxyethoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamidedi-hydrochloride salt

Prepared according to Example 57, substituting 2-tert-butoxyethanol fortert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate to give7-(2-tert-butoxyethoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide.This material was treated with TFA, followed by treatment with 2MHCl/ether to give the title compound (20 mg, 65%). MS (APCI), positivescan, m/z=457.2 (M+H).

Example 587-(2,3-dihydroxypropoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-2-amine

A sealed tube containing 4-chloro-2-pyridinamine (4 g, 31.2 mmol),(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (8.4 g, 60.6 mmol), and sodium(1.46 g, 63.5 mmol) was heated at 145° C. for 8 hours. The mixture wascooled to ambient temperature, and water (25 mL) and dichloromethane (50mL) were added. The organic phase was separated, dried with sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by chromatography by silica gel chromatography to give4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-2-amine as a paleyellow solid (5.6 g).

Step B: Preparation of ethyl7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylate

4-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)pyridin-2-amine (5.6 g, 0.025mol) was mixed with ethanol (60 mL) in a reaction flask under anatmosphere of dry nitrogen. A solution of ethyl 2-chloro-3-oxopropanoate(5% in benzene; 93 mL; Commercial solution from Toronto ResearchChemicals Inc.) was added. The mixture was heated to 60° C. undernitrogen for 2 hours. After allowing the mixture to cool the solvent wasremoved under vacuum to give a brown solid. The solid was mixed withethyl acetate (200 mL) and sodium bicarbonate solution (100 mL) andstirred to dissolve. The phases were separated and the bicarbonatesolution was extracted further with ethyl acetate (50 mL). The combinedethyl acetate extracts were dried over sodium sulfate, filtered andconcentrated under vacuum to give a solid. The crude material wasdissolved in ethyl acetate and passed through a short column of silicagel, eluting with ethyl acetate to give ethyl7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylateas a pale yellow solid (5.76 g).

Step C: Preparation of7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylicacid

Ethyl7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylate(1.8 g, 5.63 mmol) and lithium hydroxide monohydrate (0.284 g, 6.75mmol) were combined in a flask containing tetrahydrofuran/ethanol/water(1:2:1, 56 mL). After stirring overnight at ambient temperature, thesolvent was removed under vacuum to give a yellow gum. Water (20 mL) anddichloromethane were added. The aqueous layer was separated and cooledin an ice-water bath before adjusting to pH 4 with 20% citric acid. Aprecipitate formed and was collected by filtration. The solids werewashed with a small amount of water (5 mL) and dried under vacuum togive7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylicacid as a white solid (1.3 g).

Step D: Preparation of7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

7-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylicacid (66 mg, 0.23 mmol) was dissolved in dichloromethane (1 mL) and 2 Moxalyl chloride in dichloromethane (0.12 mL, 0.25 mmol) was added with adrop of dimethylformamide. The mixture was stirred at ambienttemperature for 1 hour before addition of3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (57 mg,0.23 mmol) and diisopropylethylamine (0.08 mL, 0.46 mmol), and then themixture was stirred overnight. The crude mixture was purified usingpreparative thin layer chromatography (silica, 20×20 cm, 1 mm) developedin a chamber with 10% methanol/dichloromethane to give7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(12 mg).

Step E: Preparation of7-(2,3-dihydroxypropoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

7-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(11 mg, 0.02 mmol) was taken up in 50% trifluoroacetic acid/water andstirred at ambient temperature for 1 hour. Concentrated and dried underhigh vacuum for an hour before treating with excess 2 M hydrochloricacid in diethyl ether. The solution was stirred for an hour and thenconcentrated to give7-(2,3-dihydroxypropoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideas a colorless residue (8 mg). MS m/z 487.2 (M+1, APCI+).

Example 59N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 4-(2-morpholinoethoxy)pyridin-2-amine

2-Morpholinoethanol (2.2 g, 16.8 mmol) was treated with sodium (116 mg,5.0 mmol) in a sealed tube and stirred at ambient temperature untilhomogeneous. 4-Chloropyridin-2-amine (1.1 g, 8.9 mmol) was added andreaction heated to 145° C. and stirred in sealed tube for 10 hours. Themixture was cooled to ambient temperature before diluting with ethylacetate and water. After separation of layers, the aqueous was extractedtwice more with ethyl acetate. Concentration of the reaction mixtureafforded a viscous oil which was purified on a Biotage 40+Silica column,eluting with 10% methanol/dichloromethane, to give4-(2-morpholinoethoxy)pyridin-2-amine as a viscous oil which solidifiedupon further drying under high vacuum (1.4 g).

Step B: Preparation of ethyl7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxylate

4-(2-Morpholinoethoxy)pyridin-2-amine (1.37 g, 6.14 mmol) was dissolvedin ethanol (20 mL) in round bottom flask. Ethyl 2-chloro-3-oxopropanoate(5% in benzene; 30 mL; Commercial solution from Toronto ResearchChemicals Inc.) was added and the mixture was heated to reflux withstirring overnight. The reaction was concentrated to give a beige solid(1.31 g). The solid was purified on a silica column eluting with agradient from 50-100% ethyl acetate/hexanes over 800 mL followed byelution with 10% methanol/dichloromethane to give ethyl7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxylate as a whitesolid (1 g).

Step C: Preparation of lithium7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxylate

Ethyl 7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxylate (1 g,3.13 mmol) was dissolved in tetrahydrofuran/water (4:1, 0.5 M). Lithiumhydroxide monohydrate (131 mg, 3.13 mmol) was added and the mixturestirred at ambient temperature overnight. The mixture was then furtherdiluted with tetrahydrofuran and concentrated. The resulting materialwas dried under high vacuum for 6 hours to give lithium7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxylate as a paleyellow solid (979 mg).

Step D: Preparation ofN-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Lithium 7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxylate(0.055 g, 0.186 mmol) was dissolved in dimethylformamide (0.6 mL),O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate(53 mL, 0.17 mmol),3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (Example35, Steps A-D; 0.042 g, 0.167 mmol), and diisopropylethylamine (0.058mL, 0.334 mmol) were combined in a 1 dram vial. The mixture stirred atambient temperature overnight. The crude mixture was purified usingpreparative thin layer chromatography (silica, 20×20 cm, 1 mm) developedin a chamber with 10% Methanol/dichloromethane to giveN-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxamide(6 mg). MS m/z 526.1 (M+, APCI+).

Example 607-(2-(dimethylamino)ethoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 4-(2-(dimethylamino)ethoxy)pyridin-2-amine

2-Dimethylaminoethanol (34.8 g, 39.0 mmol) was treated with sodium (2.7g, 11.7 mmol) in a sealed tube and stirred at ambient temperature untilhomogeneous. 4-Chloropyridin-2-amine (5 g, 3.9 mmol) was added andreaction heated to 150° C. and stirred in sealed tube for 8 hours. Themixture was cooled to ambient temperature before concentrating andtriturating with dichloromethane (50 mL) four times. The combinedtriturates were concentrated and purified by column chromatography togive 4-(2-(dimethylamino)ethoxy)pyridin-2-amine as a yellow solid (3.8g).

Step B: Preparation of ethyl7-(2-(dimethylamino)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate

4-(2-(Dimethylamino)ethoxy)pyridin-2-amine (0.87 g, 4.8 mmol) wasdissolved in ethanol (15 mL) in round bottom flask. Ethyl2-chloro-3-oxopropanoate (5% in benzene; 23 mL; Commercial solution fromToronto Research Chemicals Inc.) was added and the mixture refluxed for10 hours. The reaction mixture was concentrated to give a beige solid(1.31 g). The solid was purified using a Biotage silica column (25+)eluting with a gradient from 50-100% ethyl acetate/hexanes over 600 mLfollowed by 10% methanol/dichloromethane to give ethyl7-(2(dimethylamino)ethoxy) imidazo[1,2-a]pyridine-3-carboxylate as ayellow solid (1.2 g).

Step C: Preparation of7-(2-(dimethylamino)ethoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

3-Methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (59 mg,0.24 mmol) was dissolved in tetrahydropyran (DriSolve; 1.2 mL) anddegassed before back-filling with nitrogen. The solution was cooled inan ice water bath for 15 minutes before dropwise addition of lithiumbis(trimethylsilyl)amide (0.25 mL, 1 M in tetrahydrofuran). The reactionstirred for 10 minutes before dropwise addition into a solution of ethyl7-(2-(dimethylamino)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (31 mg,0.12 mmol) in tetrahydrofuran (DriSolve; 1.2 mL) cooled in an ice-waterbath. The reaction was then stirred while being cooled in the ice-waterbath for 1.5 hours. The reaction was quenched with water andconcentrated. Purification using reverse phase chromatography, elutingwith a gradient from 10% to 60% ACN/water, gave7-(2-(dimethylamino)ethoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(30 mg). MS m/z 484.1 (M+1, APCI+).

Example 61N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Imidazo[1,2-a]pyridine-3-carboxylic acid (62 mg, 0.38 mmol) wasdissolved neat in thionyl chloride (112 mL, 1.5 mmol). The reactionmixture was stirred at ambient temperature for 1 hour beforeconcentrating and drying under high vacuum for 16 hours. The resultingsolid was dissolved in tetrahydrofuran (2 mL).3-Methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (97 mg,0.38 mmol) was added and the reaction was stirred at 70° C. in a sandbath for 6 hours. The mixture was concentrated and partitioned betweenethyl acetate and saturated sodium bicarbonate. The ethyl acetate layerwas washed with water and brine before drying over sodium sulfate andconcentrating. Preparative Thin Layer Chromatography (Silica, 1 mm) ofthe crude material, eluting with 10% MeOH/DCM, gaveN-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(48 mg) in a band with Rf=0.6. MS m/z 397.3 (M+1, APCI+).

Example 626-cyano-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of ethyl 6-cyanoimidazo[1,2-a]pyridine-3-carboxylate

2-Amino-5-cyanopyridine (15.5 g, 152 mmol) was dissolved in ethanol (500mL) in 2 L round bottom flask. Ethyl 2-chloro-3-oxopropanoate (5% inbenzene; 730 mL; Commercial solution from Toronto Research ChemicalsInc.) was added and the mixture was heated at reflux for 10 hours. Themixture was concentrated under reduced pressure and the residue waspurified by silica-gel chromatography to give ethyl6-cyanoimidazo[1,2-a]pyridine-3-carboxylate as a pale yellow solid (13.9g).

Step B: Preparation of lithium6-cyanoimidazo[1,2-a]pyridine-3-carboxylate

Ethyl 6-cyanoimidazo[1,2-a]pyridine-3-carboxylate (13.9 g, 65 mmol) andlithium hydroxide monohydrate (2.7 g, 65 mmol) were dissolved intetrahydrofuran/ethanol/water (1:2:1, 150 mL:300 mL:150 mL). Afterstirring for 16 hours at ambient temperature, the solvent was removedunder vacuum to give lithium 6-cyanoimidazo[1,2-a]pyridine-3-carboxylate(12.6 g).

Step C: Lithium 6-cyanoimidazo[1,2-a]pyridine-3-carboxylate (138 mg, 0.7mmol) was dissolved in anhydrous NMP (3.6 mL) and 2,4,6-trichlorobenzoylchloride (115 mL, 0.7 mmol) added drop-wise. The mixture was stirred atambient temperature for 30 minutes.3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (186 mg,0.7 mmol) was then added in one portion and the reaction heated to 80°C. in a sand bath for 6 hours. Saturated sodium bicarbonate was addeduntil precipitate formed and allowed to stir at ambient temperature foran hour. The precipitate was filtered off and dried under high vacuumfor 2 hours to give6-cyano-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideas a beige solid (140 mg). MS m/z 422.3 (M+1, APCI+).

Example 637-hydroxy-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of ethyl7-hydroxyimidazo[1,2-a]pyridine-3-carboxylate

2-Aminopyridin-4-ol (3 g, 27 mmol) was dissolved in ethanol (90 mL) in250 mL round bottom flask. Ethyl 2-chloro-3-oxopropanoate (5% inbenzene; 130 mL; Commercial solution from Toronto Research ChemicalsInc.) was added and the mixture refluxed for 10 hours. Reaction wasconcentrated and triturated with ethyl acetate before drying under highvacuum to give ethyl 7-hydroxyimidazo[1,2-a]pyridine-3-carboxylate as abeige solid (829 mg).

Step B: Preparation of ethyl7-(ethoxymethoxy)imidazo[1,2-a]pyridine-3-carboxylate

Ethyl 7-hydroxyimidazo[1,2-a]pyridine-3-carboxylate (100 mg, 0.38 mmol)was dissolved in DMF (3 mL) and treated with potassium carbonate (79 mg,0.57 mmol). The mixture was stirred at ambient temperature for 30minutes before adding chloromethylethyl ether (40 mg, 0.42 mmol) andheating mixture to 60° C. for 1 hour. The crude mixture was purified byreverse phase chromatography to give ethyl7-(ethoxymethoxy)imidazo[1,2-a]pyridine-3-carboxylate (11 mg).

Step C: Preparation of7-(ethoxymethoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

3-Methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (22 mg,0.09 mmol) was dissolved in tetrahydropyran (DriSolve; 0.5 mL) anddegassed before back-filling with nitrogen gas. The solution was thencooled in an ice water bath for 15 minutes before drop-wise addition oflithium bis(trimethylsilyl)amide (0.09 mL, 1 M in tetrahydrofuran). Thereaction stirred for 10 minutes before drop-wise addition into asolution of ethyl 7-(ethoxymethoxy)imidazo[1,2-a]pyridine-3-carboxylate(11 mg, 0.04 mmol) in tetrahydrofuran (DriSolve; 0.2 mL) cooled in anice-water bath. The reaction was then stirred while being cooled in theice-water bath for 1.5 hours. The reaction was quenched with water andconcentrated. The resulting crude material was purified by reverse phasechromatography, eluting with a gradient from 10% to 70% ACN/water over25 column volumes, to give7-(ethoxymethoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(11.2 mg).

Step D: Preparation of7-hydroxy-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

7-(Ethoxymethoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(11.2 mg, 0.02 mmol) was dissolved in dichloromethane (0.9 mL) andtreated with trifluoroacetic acid (0.1 mL). The mixture was stirred atambient temperature for 2 hours. The mixture was concentrated and driedunder high vacuum to give7-hydroxy-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(8 mg). MS m/z 413.2 (M+1, APCI+).

Example 64N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(piperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of tert-butyl 4-fluoropyridin-2-ylcarbamate

A flask was charged with 2-chloro-4-fluoropyridine (20 g, 152 mmol),tert-butyl carbamate (89 g, 760 mmol), tris(dibenzylideneacetone)dipalladium (1.39 g, 1.52 mmol), X-PHOS (1.48 g, 3.10 mmol), cesiumcarbonate (99 g, 588 mmol), and tetrahydrofuran (500 mL) under anatmosphere of dry nitrogen. This mixture was refluxed under nitrogen for7 hours. An additional equivalent of cesium carbonate was added to drivereaction to completion. The mixture was cooled to ambient temperatureand filtered through Celite, and the Celite was washed with ethylacetate. The filtrate was partitioned between saturated sodiumbicarbonate and ethyl acetate. The aqueous layer was washed with ethylacetate twice. The combined organics were washed with brine and driedwith sodium sulfate, concentrated under vacuum, and purified by columnchromatography to give tert-butyl 4-fluoropyridin-2-ylcarbamate as apale yellow solid (22.6 g).

Step B: Preparation of 4-fluoropyridin-2-amine

A flask was charged with tert-butyl 4-fluoropyridin-2-ylcarbamate (3.5g, 16.5 mmol) and dichloromethane (100 mL). The mixture was cooled to0-5° C. using an ice/water bath. Trifluoroacetic acid (75 mL) was addedslowly down the side of the flask with continued stirring. The mixturewas stirred at ambient temperature overnight. The mixture wasconcentrated before partitioning between saturated sodium bicarbonateand ethyl acetate. The aqueous layer was washed with ethyl acetatetwice. The combined organic layers were washed with brine and dried withsodium sulfate before concentrating to give 4-fluoropyridin-2-amine as apale yellow solid (1.76 g).

Step C: Preparation of ethyl7-fluoroimidazo[1,2-a]pyridine-3-carboxylate

4-Fluoropyridin-2-amine (10.0 g, 48.0 mmol) was mixed with ethanol (40mL) in a reaction flask under an atmosphere of dry nitrogen. A solutionof ethyl 2-chloro-3-oxopropanoate (5% in benzene, 178 mL; commercialsolution from Toronto Research Chemicals Inc.) was added. The mixturewas heated to 60° C. under nitrogen for 4 hours. After allowing themixture to cool the solvent was removed under vacuum to give a brownsolid. The solid was mixed with ethyl acetate (300 mL) and sodiumbicarbonate solution (75 mL) and stirred to dissolve. The phases wereseparated and the bicarbonate solution was extracted further with ethylacetate (75 mL). The combined ethyl acetate extracts were dried oversodium sulfate, filtered and concentrated under vacuum to give a solid.The crude material was dissolved in ethyl acetate and passed through ashort column of silica, eluting with ethyl acetate to give ethyl7-fluoroimidazo[1,2-a]pyridine-3-carboxylate as a white solid (13 g).

Step D: Preparation of 7-fluoroimidazo[1,2-a]pyridine-3-carboxylic acid

Ethyl 7-fluoroimidazo[1,2-a]pyridine-3-carboxylate (8 g; 44.4 mmol) wasmixed with tetrahydrofuran (225 mL), ethanol (110 mL) and water (55 mL).Lithium hydroxide monohydrate (0.962 g; 22.9 mmol) was added. Themixture was stirred at ambient temperature overnight. The mixtureconcentrated under reduced pressure to remove tetrahydrofuran andethanol. Hydrochloric acid (2N) was added to aqueous mixture to adjustto pH 3. White precipitate formed and was filtered off with drying underhigh vacuum overnight to give7-fluoroimidazo[1,2-a]pyridine-3-carboxylic acid as a white solid (6.3g).

Step E: Preparation of7-fluoro-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

A solution of 7-fluoroimidazo[1,2-a]pyridine-3-carboxylic acid (0.15 g,0.84 mmol) in anhydrous 1-methyl-2-pyrrolidinone (4 mL) and treated withanhydrous triethylamine (0.3 mL, 2.11 mmol) allowing to stir until thereaction mixture became homogeneous. 2,4,6-Trichlorobenzoyl chloride(0.22 g, 0.89 mmol) was added dropwise and the reaction mixture wasallowed to stir for 30 minutes at ambient temperature. Within 5 minutes,the anhydride precipitate formed and vigorous stirring was required.3-Methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (Example35, Steps A-D; 0.19 g, 0.75 mmol) was added as a 0.5 M solution inanhydrous 1-methyl-2-pyrrolidinone. The reaction was heated in a sandbath at 80° C. and stirred overnight. The reaction mixture was cooled toambient temperature and solids were removed by filtration. The filtercake was washed with ethyl acetate and the filtrate was concentrated.The resulting material was diluted with saturated sodium bicarbonate anda dark brown precipitate formed. The precipitate was isolated byfiltration to give7-fluoro-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideas a brown solid (170 mg).

Step F: Preparation of tert-butyl4-(2-(3-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridin-7-yloxy)ethyl)piperazine-1-carboxylate

A flask was charged with solid potassium tert-butoxide (0.07 g, 0.64mmol), tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (0.17 g,0.74 mmol), and tert-butanol (0.6 mL). The mixture was heated to 60° C.for 20 minutes before addingN-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide(0.045 g, 0.105 mmol) in one portion. The mixture was heated in a sandbath at 80° C. with stirring overnight. The reaction mixture wasquenched with water and concentrated before purifying by reverse phasechromatography on a Biotage 25+C18 column, eluting with a gradient from0-65% acetonitrile/water over 12 column volumes, to give tert-butyl4-(2-(3-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridin-7-yloxy)ethyl)piperazine-1-carboxylate(40 mg) as a beige solid. MS (APCI), positive scan, m/z=639.1 (M+).

Step G: Preparation ofN-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(piperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

tert-Butyl4-(2-(3-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridin-7-yloxy)ethyl)piperazine-1-carboxylate(0.04 g, 0.1 mmol) was dissolved in methanol and treated withconcentrated hydrogen chloride. This mixture was stirred at ambienttemperature for 2 hours before concentrating and drying under highvacuum overnight to giveN-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(piperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamideas a white solid (38 mg). MS (APCI), positive scan, m/z=539.1 (M+).

Example 65N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

A flask was charged with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (4.204 g,16.56 mmol), potassium acetate (4.432 g, 45.15 mmol), DPPF (0.2502 g,0.4515 mmol), PdCl₂(DPPF)*dcm (0.3733 g, 0.4515 mmol), and dioxane (37mL). The mixture was degassed with house nitrogen and heated at an oilbath temperature of 80° C. with stirring overnight. The mixture wascooled to ambient temperature, diluted with ethyl acetate and saturatedsodium bicarbonate. The organic layer was dried over sodium sulfate andconcentrated. Purification using flash chromatography eluting with agradient from 0-50% ethyl acetate/hexanes to give1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-oneas a colorless oil that solidifies to off-white solid under high vacuum(331 mg). MS (APCI), positive scan, m/z=504.2 (M+).

Step B: Preparation ofN-(3-methyl-1-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamide

7-Bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(0.05 g, 0.12 mmol) was dissolved in dimethoxyethane:dimethylformamide(1:1, 0.8 mL) in a 2 dram vial, and1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(0.04 g, 0.17 mmol), PdCl₂(dppf)*dcm (0.005 g, 0.006 mmol), and 2 Msodium carbonate (0.17 mL, 0.34 mmol) were added. Nitrogen was bubbledthrough the reaction mixture for 5 minutes before capping the vial andheating in a sand bath at 90° C. overnight. The reaction mixture wasdiluted with ethyl acetate and water. A greenish precipitate formed andwas collected. The crude material was purified by preparatory thin layerchromatography (silica, 20×20 cm, 0.5 mm) developed in a chamber with10% MeOH/DCM. The UV active band with R_(f)=0.1 was isolated and thesilica washed with 10% MeOH/DCM. The filtrate was concentrated to giveN-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxamideas a beige solid (31 mg).

Example 66N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole

A first flask was charged with 1,4-dioxane/H₂O (30 mL/5 mL). The flaskwas cooled to 0° C. and vacuum was applied for 20 minutes. A secondflask was charged with K₂CO₃ (2.92 g, 21.1 mmol),3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole (1.98 g,5.28 mmol), diacetoxypalladium (0.0592 g, 0.264 mmol), methylboronicacid (0.948 g, 15.8 mmol) and sodium2′-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate (0.270 g,0.528 mmol). The second flask was evacuated with vacuum and back filledwith N₂ for 3 times. The cold degassed dioxane/H₂O was then added to thesecond flask, which was again evacuated with vacuum and back filled withargon 5 times. The reaction mixture was heated to 80° C. for 3 hours.The reaction was cooled to ambient temperature, filtered andconcentrated under reduced pressure. The residue was diluted with EtOAc(200 mL). The organic layer was washed with saturated NaHCO₃, dried(Na₂SO₄) and concentrated to give the desired product, which was usedwithout further purification.

Step B: Preparation of1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine

To a suspension of1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole (1.51g, 4.87 mmol) in EtOH/H₂O (40 mL/10 mL) was added iron (5.43 g, 97.3mmol) and ammonium chloride (0.260 g, 4.87 mmol). The reaction mixturewas heated to reflux for three hours, then cooled to 60° C. and filteredthrough a pad of Celite®. The filter cake was washed with EtOH/Et₃N(20:1, 200 mL) and MeOH/DCM (1:1, 100 mL). The filtrate wasconcentrated, and the residue was dissolved in EtOAc (200 mL). The ethylacetate was washed with NaHCO₃, dried (Na₂SO₄), filtered andconcentrated to give the desired product (57%).

Step C: Preparation ofN-(1-((6-isoproplpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 138. MS (ES+APCI) m/z=567.1(M+H).

Example 67N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 66, replacing1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole in StepB with1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-3-methyl-4-nitro-1H-indazole.MS (ES+APCI) m/z=570.2 (M+H).

Example 68N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of7-bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

To a solution of3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (197.8 mg,0.784 mmol) in anhydrous THF (3 ml) was added lithiumbis(trimethylsilyl)amide (1.0 M in THF, 1.6 mL) under a nitrogenatmosphere at ambient temperature. The resulting mixture was stirred atambient temperature for 10 minutes, then added dropwise to a chilled(ice-water bath) solution of methyl7-bromoimidazo[1,2-a]pyridine-3-carboxylate (200 mg, 0.784 mmol) inanhydrous THF (3 mL). The cold bath was removed, and the reactionmixture was allowed to warm to ambient temperature, and quenched withwater. The resulting suspension was extracted with DCM. The combinedorganic extracts were dried over anhydrous sodium sulfate andconcentrated to afford the crude product. The crude product wassubjected to preparative thin-layer chromatography on silica with 8%MeOH/DCM as the eluent to afford 255.6 mg of desired product as a yellowsolid.

Step B: Preparation ofN-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

A dried flask equipped with a reflux condenser and a nitrogen line wascharged with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(14.4 mg, 0.069 mmol),7-bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Example 50, Steps A-B; 30 mg, 0.063 mmol), Pd(PPh₃)₄(3.7 mg, 0.003mmol), and potassium carbonate (44 mg, 0.32 mmol). To the flask wasadded a water:DMF:CH₃CN (1:1:4.5; 0.16:0.16:1.0 mL) mixture, and thereaction mixture was degassed under nitrogen and heated at 80° C. for 5hours. The reaction mixture was cooled and diluted with water. Theresulting suspension was extracted with EtOAc and DCM. The combinedorganic extracts were dried over anhydrous sodium sulfate andconcentrated to afford the crude product. The crude product wassubjected to preparative thin-layer chromatography on silica with 8%MeOH/DCM as eluent to afford 12.7 mg of product as a yellow solid. MS(ES+APCI) m/z=477 (M+H) detected.

Example 697-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to procedure of Example 68, using7-bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.¹H NMR (CDCl₃, δ) 9.55 (d, 1H), 8.40 (s, 1H), 8.24 (s, 1H), 7.78 (d,1H), 7.62 (s, 1H), 7.42 (t, 1H), 7.34 (t, 1H), 7.15 (d, 1H), 7.06 (t,2H), 6.52 (d, 1H), 5.64 (s, 2H), 2.87 (s, 3H), 2.58 (s, 3 h), 2.40 (s,6H).

Example 70N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to procedure of Example 68 using7-bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideand tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate.MS (ES+APCI) m/z=463 (M+H) detected.

Example 71N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of3-methyl-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole

A flask equipped with a reflux condenser and a nitrogen line was chargedwith 3-iodo-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole(Example 89, Steps A-B; 100 mg, 0.254 mmol), trio-tolylphosphine (15.4mg, 0.051 mmol), and tris(dibenzylideneacetone)dipalladium (0) (23 mg,0.025 mmol). The flask was purged with nitrogen and anhydrous DMF (30mL), and tetramethylstannane (0.04 ml, 0.28 mmol) were added, followedby triethylamine (0.04 mL, 0.30 mmol). The flask was degassed undernitrogen and heated at 80° C. for 6 hours. The reaction mixture wascooled to ambient temperature, diluted with water, and extracted withDCM and EtOAc. The combined organic extracts were dried over anhydroussodium sulfate, and concentrated. The crude product was subjected topreparative thin-layer chromatography on silica with 2% MeOH/DCM aseluent to afford 56.8 mg of desired product as a yellow solid.

Step B: Preparation of3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine

A suspension of3-methyl-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (54 mg,0.19 mmol) in absolute EtOH (1.5 mL) was treated at ambient temperaturewith dihydroxypalladium (27 mg, 0.019 mmol). The mixture was stirred atambient temperature under a hydrogen atmosphere for 16 hours, thenfiltered through a Celite® pad and concentrated to afford 36 mg of thedesired product as a clear yellow oil.

Step C: Preparation of methyl7-bromoimidazo[1,2-a]pyridine-3-carboxylate

A 50 mL flask equipped with a reflux condenser and a nitrogen line wascharged with 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (1.00 g,4.15 mmol), DCM (20 mL), oxalyl chloride (0.72 mL, 1.46 mmol), andchilled in a ice-water bath. Four drops of DMF were added to thereaction, and the flask was stirred at ambient temperature overnight.The reaction mixture was concentrated to dryness, chilled in an icewater bath, and 30 mL MeOH were added under a nitrogen atmosphere. Thereaction mixture was stirred at ambient temperature overnight,concentrated to dryness, and re-suspended in saturated, aqueous sodiumbicarbonate solution. The suspension was extracted with DCM and EtOAc,the combined organic extracts were dried over anhydrous sodium sulfate,and concentrated to afford the desired product (0.918 g) as a tan solid.

Step D: Preparation of methyl7-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-a]pyridine-3-carboxylate

A dried flask equipped with a reflux condenser and a nitrogen line wascharged with methyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate (200 mg,0.784 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(180 mg, 0.869 mmol) and PdCl₂(dppf) dichloromethane adduct (64 mg,0.078 mmol). To the flask was added 3 mL 1,2-dimethoxyethane containing1% absolute ethanol, followed by addition of triethylamine (0.22 mL,1.57 mmol). The flask was degassed under nitrogen and heated at 85° C.for 10 hours. The reaction mixture was allowed to cool to ambienttemperature and then diluted with water. The resulting suspension wasextracted with DCM. The combined organic extracts were dried overanhydrous sodium sulfate, and concentrated to afford the crude product.The crude product was subjected to preparative thin-layer chromatographyon silica with 4% MeOH/DCM as eluent to afford 47.4 mg of pure, desiredproduct as a pale yellow solid.

Step E: Preparation ofN-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-a]pyridine-3-carboxamide

To a solution of3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (46.7 mg,0.185 mmol) in anhydrous THF (2 ml) was added under a nitrogenatmosphere at ambient temperature lithium bis(trimethylsilyl)amide (1.0M in THF, 0.38 mL). The resulting mixture was stirred at ambienttemperature for 10 minutes, then added dropwise to a chilled (ice-waterbath) solution of methyl7-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-a]pyridine-3-carboxylate (47.4mg, 0.185 mmol) in anhydrous THF (2 mL). The cold bath was removed, andthe reaction mixture was allowed to warm to ambient temperature, andquenched with water. The resulting suspension was extracted with DCM.The combined organic extracts were dried over anhydrous sodium sulfateand concentrated to afford the dried product. The crude product wassubjected to preparative thin-layer chromatography on silica with 8%MeOH/DCM as eluent to afford 45.7 mg of pure, desired product as ayellow-brown solid. MS (ES+APCI) m/z=477 (M+H) detected.

Example 727-(2-(dimethylamino)ethyl)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of(Z)-7-(2-ethoxyvinyl)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

A flask was charged with7-bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Example 50, Steps A-B; 100 mg, 0.21 mmol), tri-O-tolylphosphine (12.8mg, 0.042 mmol) and tris(dibenzylideneacetone)dipalladium (19.3 mg,0.021 mmol). To the flask was added DMF (3 mL), followed by(Z)-tributyl(2-ethoxyvinyl)stannane (114 mg, 0.316 mmol) andtriethylamine (0.04 mL, 0.30 mmol). The reaction mixture was degassedunder nitrogen, and stirred at 100° C. for 10 hours. The reactionmixture was cooled, diluted with water, and extracted with DCM andEtOAc. The combined organic extracts were dried over anhydrous sodiumsulfate and concentrated. The crude product was subjected to preparativethin-layer chromatography on silica with 5% MeOH/DCM as eluent to afford82.8 mg of product as a yellow solid.

Step B: Preparation ofN-(3-methyl-1-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-oxoethyl)imidazo[1,2-a]pyridine-3-carboxamide

A solution of(Z)-7-(2-ethoxyvinyl)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(82.8 mg, 0.177 mmol) in 1:1 dioxane/water (2 mL) was treated with 45equivalents of 4.0 M hydrochloric acid in dioxane solution at ambienttemperature. The reaction mixture was stirred at ambient temperature for1.5 hours, quenched with saturated aqueous sodium bicarbonate solution,and extracted with DCM and EtOAc. The combined organic extracts weredried over anhydrous sodium sulfate, concentrated, and subjected topreparative thin-layer chromatography on silica with a 10% MeOH in DCMsolution as eluent to afford 37 mg of the impure desired product as ayellow solid. The crude product was used in the next step withoutfurther purification.

Step C: Preparation of7-(2-(dimethylamino)ethyl)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

A solution ofN-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-oxoethyl)imidazo[1,2-a]pyridine-3-carboxamide(33 mg, 0.068 mmol) and dimethylamine (0.34 mL, 0.68 mmol) in 1.4 mL ofa 1:1 MeOH/EtOH mixture was treated at ambient temperature with excess(10 equivalents) sodium triacetoxyborohydride. The reaction mixture wasstirred overnight at ambient temperature. Another 10 equivalents ofsodium triacetoxyborohydride were added, and stirring was continued fora few more hours. The reaction mixture was quenched with an equal volumeof saturated, aqueous sodium bicarbonate, and extracted with DCM andEtOAc. The combined organic extracts were dried over anhydrous sodiumsulfate, concentrated, and subjected to preparative thin-layerchromatography on silica, with an 8% MeOH-2% 7N NH₃/MeOH/DCM mixture aseluent, to afford 6.6 mg of desired product. MS (ES+APCI) m/z=468 (M+H)detected.

Example 737-(2-hydroxyethyl)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

A solution ofN-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-oxoethyl)imidazo[1,2-a]pyridine-3-carboxamide(5 mg, 0.011 mmol) in 0.5 mL absolute EtOH was treated at ambienttemperature with 3 equivalents of sodium triacetoxyborohydride. Thereaction mixture was stirred overnight at ambient temperature, afterwhich another 10 equivalents reducing agent were added. Stirring wascontinued until starting material was consumed. The reaction wasquenched with excess saturated aqueous sodium bicarbonate solution, andextracted with DCM and EtOAc. The combined organic extracts were driedover anhydrous sodium sulfate, and concentrated. The crude product wassubjected to preparative thin-layer chromatography on silica with 5%MeOH/DCM as eluent to afford 3.7 mg of product as a white solid. MS(ES+APCI) m/z=441 (M+H) detected.

Example 747-(2-(2-methoxyethylamino)ethyl)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to procedure for Example 72 fromN-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-oxoethyl)imidazo[1,2-a]pyridine-3-carboxamideand 2-methoxyethanamine. MS (ES+APCI) m/z=498 (M+H) detected.

Example 757-(1-(2-hydroxyethylamino)ethyl)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared from7-acetyl-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Example 79) and ethanolamine following procedure in Example 72, Step C.MS (ES+APCI) m/z=484 (M+H) detected.

Example 767-(1-hydroxyethyl)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Isolated as a by-product from preparation of Example 75. MS (ES+APCI)m/z=441 (M+H) detected.

Example 77N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(pyrrolidin-1-yl)ethyl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to procedure of Example 72 fromN-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-oxoethyl)imidazo[1,2-a]pyridine-3-carboxamide(Example 72, Steps A-B) and pyrrolidine. MS (ES+APCI) m/z=494 (M+H)detected.

Example 78N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethyl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to procedure for Example 72 fromN-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-oxoethyl)imidazo[1,2-a]pyridine-3-carboxamideand 1-methylpiperazine. MS (ES+APCI) m/z=523 (M+H) detected.

Example 797-acetyl-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of7-(1-ethoxyvinyl)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

A flask equipped with a reflux condenser and a nitrogen line was chargedwith7-bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Example 50, Steps A-B; 74.8 mg, 0.157 mmol), tri-O-tolylphosphine (9.6mg, 0.031 mmol), and tris(dibenzylideneacetone)dipalladium (0) (14.4 mg,0.015 mmol). Anhydrous DMF (2 mL), tributyl(1-ethoxyvinyl)tin (0.07 mL,0.22 mmol) and triethylamine (0.03 mL, 0.22 mmol) were added to theflask, and the reaction mixture was degassed under nitrogen and stirredat 100° C. for 6 hours. The reaction mixture was cooled, diluted withexcess water and extracted with DCM and EtOAc. The combined organicswere dried over anhydrous sodium sulfate and concentrated. The crudeproduct was purified by preparative thin-layer chromatography (silica,5% MeOH/DCM as eluent) to afford 56.4 mg of desired product as a yellowsolid.

Step B: Preparation7-acetyl-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

A solution of7-(1-ethoxyvinyl)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(56.4 mg, 0.121 mmol) in DCM (1 mL) was treated at ambient temperaturewith a 4.0 M solution of HCl in dioxane (10 equivalents). The reactionmixture was stirred at ambient temperature for 0.5 hours, then quenchedwith saturated aqueous sodium bicarbonate. The resulting suspension wasextracted with DCM and EtOAc. The combined organic extracts were driedover anhydrous sodium sulfate and concentrated. The crude product waspurified by preparative thin-layer chromatography (silica, 5% MeOH/DCMas eluent) to afford 24 mg of desired product as a solid. MS (ES+APCI)m/z=439 (M+H) detected.

Example 80N-(1-benzyl-3-methyl-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 3-iodo-4-nitro-1H-indazole

Prepared according to the method of Example 89.

Step B: Preparation of 3-methyl-4-nitro-1H-indazole

A solution of dimethyl zinc (1.73 ml, 3.46 mmol) was added dropwise to amixture of 3-iodo-4-nitro-1H-indazole (0.500 g, 1.73 mmol) and(1,1′-bis(diphenylphosphino)ferrocene) dichloropalladium (0.427 g, 0.519mmol) in dioxane (0.2M, 9 mL) under argon. The mixture was heated underreflux for 2 hours. After cooling, MeOH (<1 mL) was added, followed by2N HCl (1 mL) and DCM (5 mL). After stirring mixture for 30 minutes, theorganic layer was separated, washed with saturated aqueous sodiumbicarbonate, water, and brine. The combined organic extracts were dried(phase separator silicone treated filter paper), concentrated andpurified on silica gel (1-10% EtOAc in DCM to provide3-methyl-4-nitro-1H-indazole (0.082 g, 27% yield) as a brown residue.

Step C: Preparation of 1-benzyl-3-methyl-4-nitro-1H-indazole

To a solution of 3-methyl-4-nitro-1H-indazole (0.100 g, 0.564 mmol) inacetone (0.4M, 1.4 mL) cooled to 0° C. was added potassium hydroxide(0.0475 g, 0.847 mmol). After 15 minutes at 0° C., (bromomethyl)benzene(0.0737 ml, 0.621 mmol) was added. The mixture was allowed to stir atambient temperature overnight and then concentrated. The residue waspurified on silica gel (10-50% EtOAc in hexanes) to provide1-benzyl-3-methyl-4-nitro-1H-indazole (0.052 g, 34% yield) as a yellowgum.

Step D: Preparation of 1-benzyl-3-methyl-1H-indazol-4-amine

A solution of 1-benzyl-3-methyl-4-nitro-1H-indazole (0.052 g, 0.19mmol), ammonium chloride (0.0052 g, 0.097 mmol) in 4:1 EtOH/water (5 mL)was treated with iron (0.11 g, 1.9 mmol) and refluxed for 2 hours. Themixture was concentrated and residue shaken in EtOAc/water, filteredthrough GF/F paper, and concentrated to provide1-benzyl-3-methyl-1H-indazol-4-amine (0.46 g, 82% yield) as a yellowgum.

Step E: Preparation ofN-(1-benzyl-3-methyl-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide

A mixture of 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid(0.035 g, 0.148 mmol) in dichloromethane (10 mL) was added oxalylchloride in dichloromethane (2M, 0.081 mL, 0.163 mmol) with a catalytic(drop) amount of DMF. After stirring at ambient temperature for 30minutes, 1-benzyl-3-methyl-1H-indazol-4-amine (0.0387 g, 0.163 mmol) wasadded (as a solution in 1 mL methylene chloride), followed bydiisopropylethylamine (0.0310 mL, 0.178 mmol). The mixture was stirredovernight and then partitioned between water and DCM. The combinedorganic extracts were dried (phase separator silicone treated filterpaper), evaporated in vacuum and purified on silica gel (10-50% EtOAc inhexanes) to affordN-(1-benzyl-3-methyl-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide(0.022 g, 33% yield) as a white solid, 22 mg. MS (APCI) m/z=456 (M+H).

Example 81N-(3-methyl-1-((6-methylpyridin-3-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of (6-methylpyridin-3-yl)methanol

A solution of methyl 6-methylnicotinate (16.3 g, 108 mmol) in MeOH (150mL) was treated with sodium borohydride (12.2 g, 323 mmol) at ambienttemperature in portions. The mixture was quenched with water (100 mL)and concentrated. This mixture was diluted with water (300 mL) andextracted with EtOAc. The combined organic extracts were dried (phaseseparator silicone treated filter paper) and concentrated to give(6-methylpyridin-3-yl)methanol (8.5 g, 64% yield) as a light yellow oil.

Step B: Preparation of 5-(chloromethyl)-2-methylpyridine hydrochloride

(6-Methylpyridin-3-yl)methanol (8.54 g, 69.34 mmol) was dissolved intoluene (0.5M, 125 mL). Thionyl chloride (10.12 mL, 138.7 mmol) wasadded dropwise, during which a white solid began to precipitate out ofsolution. The mixture was heated to 65° C. and stirred for 1 hour. Themixture was concentrated, shaken in ether and collected by filtration toprovide 5-(chloromethyl)-2-methylpyridine hydrochloride (11.3 g, 92%yield) as a beige solid.

Step C: Preparation of3-methyl-1-((6-methylpyridin-3-yl)methyl)-4-nitro-1H-indazole

Prepared according to the method of Example 80, replacing(bromomethyl)benzene with 5-(chloromethyl)-2-methylpyridinehydrochloride.

Step D: Preparation of3-methyl-1-((6-methylpyridin-3-yl)methyl)-1H-indazol-4-amine

Prepared according to the method of Example 80, replacing1-benzyl-3-methyl-4-nitro-1H-indazole with3-methyl-1-((6-methylpyridin-3-yl)methyl)-4-nitro-1H-indazole.

Step E: Preparation ofN-(3-methyl-1-((6-methylpyridin-3-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 80, replacing7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid and1-benzyl-3-methyl-1H-indazol-4-amine withimidazo[1,2-a]pyridine-3-carboxylic acid and3-methyl-1-((6-methylpyridin-3-yl)methyl)-1H-indazol-4-amine (8 mg, 11%yield). MS (APCI) m/z=397 (M+H).

Example 827-(2-methoxyethoxy)-N-(3-methyl-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 80, replacing1-benzyl-3-methyl-1H-indazol-4-amine with3-methyl-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indazol-4-amine. MS(APCI) m/z=464 (M+H).

Example 837-(2-methoxyethoxy)-N-(3-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 80, replacing1-benzyl-3-methyl-1H-indazol-4-amine with3-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazol-4-amine. MS(APCI) m/z=464 (M+H).

Example 84N-(1-(cyclopropylmethyl)-3-methyl-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 80, replacing1-benzyl-3-methyl-1H-indazol-4-amine with1-(cyclopropylmethyl)-3-methyl-1H-indazol-4-amine. MS (APCI) m/z=420(M+H).

Example 85N-(3-methyl-1-((6-methylpyridin-3-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 80, replacing7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid and1-benzyl-3-methyl-1H-indazol-4-amine with3-methyl-1-((6-methylpyridin-3-yl)methyl)-1H-indazol-4-amine and lithium7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate,respectively. MS (APCI) m/z=539 (M+H).

Example 86N-(1-((6-ethoxypyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-methylpiprazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of ethyl 6-ethoxypicolinate

Iodoethane (6.90 mL, 86.3 mmol) was added to a suspension of6-hydroxypicolinic acid (3.0 g, 21.6 mmol) and silver carbonate (11.9 g,43.1 mmol) in chloroform (0.1M, 200 mL). The mixture was allowed to stirat ambient temperature for 18 hours. Insoluble material was removed byfiltration and the solid was washed with chloroform. The filtrate wasconcentrated to give ethyl 6-ethoxypicolinate (4.14 g, 98% yield) asreddish oil.

Step B: Preparation of (6-ethoxypyridin-2-yl)methanol

Sodium borohydride (16.0 g, 424 mmol) was added in portions over 35minutes to ethyl 6-ethoxypicolinate (4.14 g, 21.2 mmol) in EtOH (0.2M,200 mL). The resulting mixture was stirred at ambient temperature fortwo days. The mixture was concentrated and the residue was distributedbetween water and DCM. The organic layer was dried (phase separatorsilicone treated filter paper), and concentrated to give(6-ethoxypyridin-2-yl)methanol (3.05 g, 94% yield) as a pale yellow oil.

Step C: Preparation of 2-(chloromethyl)-6-ethoxypyridine hydrochloride

(6-Ethoxypyridin-2-yl)methanol (3.00 g, 19.6 mmol) was dissolved intoluene (0.5M, 40 mL). Thionyl chloride (2.86 ml, 39.2 mmol) was addeddropwise, during which a white solid began to precipitate out ofsolution. The mixture was heated to 65° C. with stirring for 1 hour. Themixture was concentrated and the residue shaken with ether and collectedby filtration to afford 2-(chloromethyl)-6-ethoxypyridine hydrochloride(1.2 g, 29% yield).

Step D: Preparation of3-bromo-1-((6-ethoxypyridin-2-yl)methyl)-4-nitro-1H-indazole

To a solution of 3-bromo-4-nitro-1H-indazole (1.5 g, 6.20 mmol) in DMF(0.5M, 12 mL) was added potassium carbonate (1.71 g, 12.4 mmol) atambient temperature. After 15 minutes, 2-(chloromethyl)-6-ethoxypyridinehydrochloride (1.29 g, 6.20 mmol) was added. The mixture was allowed tostir at ambient temperature for 18 hours. The mixture was concentratedand diluted with ice-water (300 mL). Precipitated solids were collectedby filtration, washed with water and dried under high vacuum overnightto provide 3-bromo-1-((6-ethoxypyridin-2-yl)methyl)-4-nitro-1H-indazole(1.21 g, 52% yield).

Step E: Preparation of1-((6-ethoxypyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole

A solution of3-bromo-1-((6-ethoxypyridin-2-yl)methyl)-4-nitro-1H-indazole (0.500 g,1.33 mmol) in dioxane (0.2M, 7 mL) was treated with potassium carbonate(0.916 g, 6.63 mmol), methylboronic acid (0.793 g, 13.3 mmol), water(0.239 mL, 13.3 mmol), followed by tetrakis(triphenylphosphine)palladium(0) (0.0766 g, 0.0663 mmol) at ambient temperature, purging under argon.The mixture was refluxed overnight, cooled to ambient temperature,filtered through glass fiber filter paper, concentrated and purified onsilica (10-75% EtOAc in hexanes) to give1-((6-ethoxypyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole (0.118 g,28% yield).

Step F: Preparation of1-((6-ethoxypyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine

A solution of1-((6-ethoxypyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole (0.118 g,0.378 mmol), ammonium chloride (0.0101 g, 0.189 mmol) in 4:1 EtOH/water(2 mL) was treated with iron (0.211 g, 3.78 mmol) and refluxed for 2hours. The solvent was removed and the residue taken in EtOAc-water andfiltered through glass fiber filter paper. The organic phase wasseparated, dried (phase separator silicone treated filter paper), andconcentrated to provide1-((6-ethoxypyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine (0.076 g,71% yield) as a yellow gum.

Step G: Preparation ofN-(1-((6-ethoxypyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 85, replacing3-methyl-1-((6-methylpyridin-3-yl)methyl)-1H-indazol-4-amine with1-((6-ethoxypyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine. MS (APCI)m/z=569 (M+H).

Example 87N-(1-((6-methoxypyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of (6-methoxypyridin-2-yl)methanol

A cold solution of 6-methoxypicolinic acid (1.8 g, 11.8 mmol) intetrahydrofuran (0.3M, 40 mL) was treated with lithium aluminum hydride(11.8 mL, 11.8 mmol) at 0° C. This mixture was stirred at 0° C. for 30minutes, poured into a beaker containing aqueous saturated Rochelle'ssalt and stirring at ambient temperature continued for 1 hour. Theproduct was extracted from EtOAc, dried (phase separator siliconetreated filter paper) paper, concentrated (1.13 g, 69% yield) as a clearoil.

Step B: Preparation of 2-(chloromethyl)-6-methoxypyridine hydrochloride

Prepared according to Example 86, Step C, replacing(6-Ethoxypyridin-2-yl)methanol with (6-methoxypyridin-2-yl)methanol.

Step C: Preparation of3-bromo-1-((6-methoxypyridin-2-yl)methyl)-4-nitro-1H-indazole

Prepared according to Example 86, Step D, replacing2-(chloromethyl)-6-ethoxypyridine hydrochloride with2-(chloromethyl)-6-methoxypyridine hydrochloride.

Step D: Preparation of1-((6-methoxypyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole

Prepared according to Example 86, Step E, replacing3-bromo-1-((6-ethoxypyridin-2-yl)methyl)-4-nitro-1H-indazole with3-bromo-1-((6-methoxypyridin-2-yl)methyl)-4-nitro-1H-indazole.

Step E: Preparation of1-((6-methoxypyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine

Prepared according to Example 86, Step F, replacing1-((6-ethoxypyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole with1-((6-methoxypyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole.

Step F: Preparation ofN-(1-((6-methoxypyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to Example 86, Step G, replacing1-((6-ethoxypyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine with1-((6-methoxypyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine. MS (APCI)m/z=555 (M+H).

Example 88N-(3-methyl-1-((2-methylthiazol-4-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 86, replacing1-((6-ethoxypyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine in Step Fwith 3-methyl-1-((2-methylthiazol-4-yl)methyl)-1H-indazol-4-amine. MS(APCI) m/z=545 (M+H).

Example 89N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamidetetrahydrochloride

Step A: Preparation of 3-iodo-4-nitro-1H-indazole

A solution of 4-nitro-1H-indazole (50.0 g; 306 mmol) in DMF (600 mL) wascooled to 5° C. under a nitrogen atmosphere with stirring. Powderedpotassium hydroxide (68.8 g; 1226 mmol) was added. A solution of iodine(156 g; 613 mmol) in DMF (200 mL) was added slowly to the reactionmixture over 2 hours maintaining the temperature between 5 and 10° C.The mixture was stirred at 25° C. for 24 hours. Additional iodine (39.0g; 153.2 mmol) and potassium hydroxide (17.2 g; 306.5 mmol) were added.The mixture was stirred at 25° C. for an additional 12 hours. Thereaction mixture was added to an aqueous solution of sodium bisulfite(10% solution; 3300 mL) with stirring. The resulting precipitate wascollected by filtration and washed with water. The material was dried ina vacuum oven at 40° C. The material was dissolved in methylenechloride/methanol (10:1; 1.5 L) and filtered through Celite® to removeinorganic impurities. Concentration of the solution under vacuum gave3-iodo-4-nitro-1H-indazole as a yellow solid (75 g).

Step B: Preparation of3-iodo-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole

To a solution of 3-iodo-4-nitro-1H-indazole (172 mg, 0.596 mmol) in dryDMF (3 mL) under an atmosphere of dry nitrogen was added2-(bromomethyl)-6-methylpyridine (122 mg, 0.656 mmol) and potassiumcarbonate (165 mg, 1.19 mmol) with stirring. The mixture was stirred atambient temperature for 3 days. The reaction mixture was diluted withwater (20 mL) and extracted into ethyl acetate. The organic phases werecombined, washed with saturated sodium chloride solution, dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresulting material was purified using preparative chromatography onsilica, eluting with hexane/ethyl acetate (3:1) to give3-iodo-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (213 mg).

Step C: Preparation of3-methyl-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole

A dried flask equipped with a reflux condenser and a nitrogen line wascharged with 3-iodo-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole(100 mg, 0.254 mmol), tri-o-tolylphosphine (15.4 mg, 0.051 mmol), andtris(dibenzylideneacetone)dipalladium (0) (23 mg, 0.025 mmol). The flaskwas purged with nitrogen and anhydrous DMF (30 mL) andtetramethylstannane (0.04 mL, 0.28 mmol) were added, followed bytriethylamine (0.04 mL, 0.30 mmol). The flask was degassed undernitrogen and heated at 80° C. for 6 hours. The reaction mixture wascooled to ambient temperature, diluted with water, and extractedmultiple times with DCM and EtOAc. The combined organic extracts weredried over anhydrous sodium sulfate and concentrated under reducedpressure. The crude product was subjected to preparative thin-layerchromatography on silica with 2% MeOH/DCM as eluent to afford 56.8 mg ofdesired product as a yellow solid.

Step D: Preparation of3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine

A suspension of3-methyl-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (54 mg,0.19 mmol) in absolute EtOH (1.5 mL) was treated at ambient temperaturewith 10% palladium hydroxide on carbon (27 mg, 0.019 mmol). The mixturewas stirred at ambient temperature under a hydrogen atmosphere for 16hours, and then filtered through a Celite(R pad, washing with EtOH. Thefiltrate was concentrated under reduced pressure to afford the product(36 mg) as a yellow oil.

Step E: Preparation ofN-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamidetetrahydrochloride

To a cooled (0° C.) solution of3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (1.67 g;6.62 mmol) in anhydrous THF (10 mL) under nitrogen was added lithiumbis(trimethylsilyl)amide (6.50 mL; 1.0M solution in THF; 6.50 mmol)dropwise over 3 minutes with vigorous stirring. The reaction mixture wasstirred with ice/water cooling for 10 minutes. A solution of ethyl7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate(Preparation A; 1.00 g; 3.01 mmol) in anhydrous THF (10 mL) was addeddropwise by syringe over 8 minutes, and the syringe was rinsed with THF(1 mL). The mixture was stirred in an ice/water bath for 30 minutes. Themixture was quenched with water (50 mL) and saturated aqueous ammoniumchloride solution (50 mL). The mixture was extracted with DCM (150 mL).Brine solution was added to the aqueous phase (150 mL) which was thenfurther extracted with DCM (100 mL). The pH of the aqueous phase wasthen adjusted to pH 10-11 with 2N NaOH solution. The aqueous layer wasthen further extracted with DCM (50 mL) and ethyl acetate (50 mL). Thecombined organic phases were washed with brine (100 mL). The brinesolution was back extracted with DCM (25 mL). The combined organicphases were dried over sodium sulfate (50 g), filtered and concentratedunder reduced pressure. The residue was purified by silica gelchromatography, eluting with 7N ammonium hydroxide inmethanol/Methanol/DCM (20/80/900) to give a yellow solid which wastriturated with ether (2×25 mL). The material was then precipitated froma minimal volume of DCM (cooling to 4° C. to precipitate) to give a paleyellow solid which was dried under vacuum at 38° C. for 16 hours). Thismaterial (1.05 g) was dissolved in methanol and an excess of HCl (2M inether) was added. The solvent was removed under vacuum and dried underhigh vacuum for 16 hours to giveN-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamidetetrahydrochloride as an off white solid (1.20 g). ¹H NMR CD₃OD δ 9.61(d, 1H), 8.81 (s, 1H), 8.34 (t, 1H), 7.86 (d, 1H), 7.64 (d, 1H), 7.54(m, 2H), 7.44 (dd, 1H), 7.32 (d, 1H), 7.25 (d, 1H), 5.97 (s, 2H), 4.81(t, 2H), 3.91 (t, 2H), 3.81 (bs, 8H), 3.04 (s, 3H), 2.87 (s, 3H), 2.61(s, 3H).

Example 90N-(1-benzyl-1H-indazol-4-yl)-7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 4-(2-morpholinoethoxy)pyridin-2-amine

2-Morpholinoethanol (2.21 g, 16.8 mmol) was treated with sodium (0.407g, 17.7 mmol) until a homogeneous suspension was obtained.4-Chloropyridin-2-amine (1.14 g, 8.86 mmol) was added and the mixturewas heated with magnetic stirring at 145° C. in a sealed tube for 10hours. The reaction mixture was cooled and diluted with water and EtOAc.The layers were separated, and the aqueous phase was extracted twicewith EtOAc. The combined organic extracts were concentrated to afford aviscous oil which was subjected to chromatographic purification onsilica with 10% MeOH/DCM as eluent to provide 1.37 g of desired productas a low-melting solid.

Step B: Preparation of ethyl7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxylate

4-(2-Morpholinoethoxy)pyridin-2-amine (1.37 g, 6.14 mmol) was dissolvedin ethanol (20 ml) and treated with ethyl 2-chloro-3-oxopropanoate (5%solution in benzene, 30 mL). The mixture was refluxed overnight. Thereaction mixture was cooled and concentrated to afford a beige solid(1.31 g), which was purified by chromatography on silica, eluting with agradient from 50% EtOAc/Hexanes to 100% EtOAc, followed by 10% MeOH/DCMto provide 1.0 g of the desired product as a white solid.

Step C: Preparation of lithium7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxylate ethyl7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxylate

Ethyl 7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxylate4-(2-morpholinoethoxy)pyridin-2-amine (1.0 g, 3.13 mmol) was dissolvedin a 4:1 THF/water mixture (to a 0.5 M concentration). Lithium hydroxidemonohydrate (75 mg, 3.13 mmol) was added and the resulting mixture wasstirred overnight at ambient temperature, followed by heating at 65° C.for eight hours. An additional 0.1 equivalents of lithium hydroxidemonohydrate was added, and heating at 65° C. was continued overnight.The reaction mixture was diluted with THF, filtered, concentrated, anddried under high vacuum to afford the crude product (0.979 g) as a paleyellow, free flowing solid.

Step D: Preparation ofN-(1-benzyl-1H-indazol-4-yl)-7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxamide

To a suspension of lithium7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxylate (42 mg, 0.142mmol) in DCM were added oxalyl chloride (1.1 equivalents) and a drop ofDMF. The mixture was stirred until gas evolution stopped. To thereaction mixture were then added 1-benzyl-1H-indazol-4-amine (31.6 mg,0.142 mmol) and Hunig's base (1.2 equivalents). The reaction was stirredat ambient temperature for two hours and then concentrated. The residuewas triturated with diethyl ether followed by chromatographicpurification on silica with 10% MeOH/DCM as eluent to provide 8.6 mg ofthe desired product as a white solid. MS (ES+APCI) m/z=497 (M+H)detected.

Example 91N-(1-benzyl-1H-indazol-4-yl)-7-(2,3-dihydroxypropoxy)imidazo[1,2-a]pyridine-3-carboxamide

A DCM solution of7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylicacid (Example 58, Steps A-C; 109.7 mg, 0.375 mmol) was treated atambient temperature with oxalyl chloride (1.1 equivalents) and a drop ofDMF. After gas evolution ceased, 1-benzyl-1H-indazol-4-amine (83.8 mg,0.375 mmol) and Hunig's base (1.2 equivalents) were added, and stirringcontinued overnight. The resulting mixture was concentrated, andtriturated with diethyl ether, followed by chromatographic purificationon silica with 10% MeOH/DCM as eluent to provide 25.2 mg of the desiredproduct. MS (ES+APCI) m/z=458 (M+H) detected.

Example 92N-(1-benzyl-1H-indazol-4-yl)-7-hydroxyimidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of ethyl7-hydroxyimidazo[1,2-a]pyridine-3-carboxylate

To a chilled (0° C.) solution of potassium2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (16.4 g, 86.3 mmol) inconcentrated sulfuric acid (43.5 mmol) and ethanol (50 mL) was added2-aminopyridin-4-ol (3 g, 27 mmol). The resulting mixture was warmed toambient temperature and refluxed for 10 hours. The reaction wasconcentrated and suspended in EtOAc. The solids were isolated to afford829 mg of pure product. The supernatant was concentrated, and subjectedto chromatography on silica with 30% EtOAc/Hexanes as eluent to afford asecond batch of desired product (5.8 g, 80% purity) as a brown, viscousoil.

Step B: Preparation of 7-hydroxyimidazo[1,2-a]pyridine-3-carboxylic acid

A solution of 7-hydroxyimidazo[1,2-a]pyridine-3-carboxylate (414 mg,2.01 mmol) in a 2:1:1 THF/ethanol/water mixture (36 mL) was treated atambient temperature with lithium hydroxide monohydrate (2.1equivalents). The reaction mixture was stirred at ambient temperatureovernight. To the reaction were then added another 2.1 equivalents oflithium hydroxide monohydrate and stirring continued for 72 hours. Afterremoval of the volatiles the mixture was diluted with water, cooled inan ice bath, and the pH adjusted to 4 with aqueous 6N hydrochloric acid.The resulting white precipitate was isolated and dried to afford thedesired product (358 mg).

Step C: Preparation ofN-(1-benzyl-1H-indazol-4-yl)-7-hydroxyimidazo[1,2-a]pyridine-3-carboxamide

A suspension of EDCI (192 mg, 0.679 mmol), 2,4,6-trimethylpyridine (224mg, 1.85 mmol), and 7-hydroxyimidazo[1,2-a]pyridine-3-carboxylic acid(110 mg, 0.617 mmol) in DMF (2 mL) was stirred at ambient temperaturefor two hours. A solution of 1-benzyl-1H-indazol-4-amine (138 mg, 0.617mmol) in DMF (2 mL) was added, and the resulting mixture was sonicatedfor 5 minutes. The heterogeneous mixture was stirred at ambienttemperature overnight, then diluted with EtOAc, and washed twice with 1Maqueous hydrochloric acid, followed by brine. The organic layer wasconcentrated and subjected to chromatography on silica with 10% MeOH/DCMas eluent to provide 1.5 mg of desired product. MS (ES+APCI) m/z=384(M+H) detected.

Example 93 Methyl3-((4-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)benzoate

Step A: Preparation of methyl3-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)benzoate

To a slurry of 3-iodo-4-nitro-1H-indazole (1.0 g, 3.46 mmol) and methyl3-(bromomethyl)benzoate (1.59 g, 6.92 mmol) and CH₃CN (12 mL) was added2-tert-butyl-1,1,3,3-tetramethylguanidine (0.697 mL, 3.46 mmol)dropwise, and the mixture was allowed to stir overnight at ambienttemperature. The mixture was then concentrated and diluted withsaturated aqueous NH₄Cl (40 mL) and EtOAc (70 mL). The organic layer wasseparated and the aqueous phase was extracted with EtOAc (25 mL). Thecombined organic extracts were washed with brine, then dried overNa₂SO₄, filtered and concentrated. The crude product was purified bycolumn chromatography (50% EtOAc/hexane) to provide 1.04 g (68%) of theproduct as a yellow/orange solid.

Step B: Preparation of methyl3-((4-amino-1H-indazol-1-yl)methyl)benzoate

A suspension of methyl3-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)benzoate (1.00 g, 2.29 mmol)and MeOH (45 mL) was cooled to 0° C. Zinc dust (0.748 g, 11.4 mmol) wasadded followed by saturated aqueous NH₄Cl (23 mL). The mixture wasstirred at 0° C. for 2 hours, then warmed to ambient temperature andstirred for an additional 3 hours. The mixture was diluted with MeOH andfiltered. To the filtrate was added saturated aqueous NH₄OAc and themixture was concentrated to remove bulk MeOH. The concentrated mixturewas extracted with EtOAc and the combined organic extracts were washedwith saturated aqueous NaHCO₃ and brine, then dried over Na₂SO₄,filtered and concentrated. The product was purified by columnchromatography (25 to 100% EtOAc/hexane) to afford 0.398 g (61%) of thetitle compound as a sticky orange foam.

Step C: Preparation of methyl3-((4-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)benzoate

To a vial was added7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (0.260 g,1.05 mmol) and NMP (3.5 mL). Triethylamine (0.243 mL, 1.74 mmol) wasadded and the mixture was stirred until homogeneous.2,4,6-Trichlorobenzoyl chloride (0.153 mL, 0.975 mmol) was added and themixture was stirred at ambient temperature for 0.5 hours. Methyl3-((4-amino-1H-indazol-1-yl)methyl)benzoate (0.196 g, 0.697 mmol) wasadded as a NMP solution (1.2 mL), and the reaction mixture was sealed inthe vial and warmed to 80° C. with stirring overnight. The reactionmixture was cooled and diluted with EtOAc (20 mL), and then filtered toremove white solids. The solids were washed with EtOAc and the filtratewas concentrated under vacuum until only DMA was left. The concentratedsolution diluted with water/saturated aqueous NaHCO₃ (25 mL, 1:1)forming a precipitate. The precipitate was isolated by filtration andthe solid was washed with water, Et₂O, and hexanes, then dried undervacuum at 40° C. for 4 hours to provide 0.279 g (74%) of the titlecompound. MS (ES+APCI) m/z=500 (M+H).

Example 94N-(1-(3-carbamoylbenzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide

To a vial was added3-((4-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)benzoicacid (0.020 g, 0.0412 mmol), HOBT (0.00612 g, 0.0453 mmol) and EDCI(0.00869 g, 0.0453 mmol) followed by THF (0.500 mL).Diisopropylethylamine (0.00789 mL, 0.0453 mmol) was added and themixture was stirred for 15 minutes. Ammonium carbonate (0.0119 g, 0.124mmol) was added in one portion and the mixture was stirred vigorouslyovernight. The mixture was diluted with water and the resultingprecipitate was isolated by vacuum filtration and washed with water. Thesolid was isolated and slurried in Et₂O and filtered and the solid waswashed with Et₂O and hexanes, then dried under vacuum (0.025 g). Thecrude solid was purified by preparative TLC (10% MeOH/CH₂Cl₂) whichprovided 0.003 g (15%) of the desired product. MS (ES+APCI) m/z=485(M+H).

Example 957-(2-Methoxyethoxy)-N-(1-(3-(methylcarbamoyl)benzyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

To a vial was added methyl3-((4-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)benzoate(Example 93; 0.026 g, 0.0521 mmol) followed by methylamine (0.972 mL,7.81 mmol, 33% in EtOH) and the mixture was sealed and heated to 50° C.with stirring for 8 hours. Additional methyl amine (0.972 mL, 7.81 mmol)was added and the mixture was stirred at 50° C. overnight. The mixturewas cooled to ambient temperature and purified directly by preparativeTLC (10% MeOH/CH₂Cl₂), providing 0.014 g (54%) of the product as a tanpowder. MS (ES+APCI) m/z=499 (M+H).

Example 96 Methyl3-((4-(7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)benzoatedihydrochloride

Step A: Preparation of methyl3-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)benzoate

To a slurry of 3-iodo-4-nitro-1H-indazole (1.0 g, 3.46 mmol) and methyl3-(bromomethyl)benzoate (1.59 g, 6.92 mmol) and CH₃CN (12 mL) was added2-tert-butyl-1,1,3,3-tetramethylguanidine (0.697 mL, 3.46 mmol) dropwiseand the mixture was allowed to stir overnight at ambient temperature.The mixture was concentrated and diluted with saturated aqueous NH₄Cl(40 mL) and EtOAc (70 mL). The layers were mixed and separated and theaqueous phase was extracted with EtOAc (25 mL). The combined organicextracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by column chromatography(50% EtOAc/hexane) to provide 1.04 g (68%) of the product as ayellow/orange solid.

Step B: Preparation of methyl3-((4-amino-1H-indazol-1-yl)methyl)benzoate

A suspension of methyl3-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)benzoate (1.00 g, 2.29 mmol)and MeOH (45 mL) was cooled to 0° C. Zinc dust (0.748 g, 11.4 mmol) wasadded followed by saturated aqueous NH₄Cl (23 mL). The mixture wasstirred at 0° C. for 2 hours, then warmed to ambient temperature withstirring for an additional 3 hours. The mixture was diluted with MeOHand filtered. To the filtrate was added saturated aqueous NH₄OAc and themixture was concentrated to remove bulk MeOH. The mixture was extractedwith EtOAc and the combined organic extracts were washed with saturatedaqueous NaHCO₃ followed by brine, dried over Na₂SO₄, filtered andconcentrated. The product was purified by column chromatography (25 to100% EtOAc/hexane) to afford 0.398 g (61%) of the title compound as asticky orange foam.

Step C: Preparation of methyl3-((4-(7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)benzoatedihydrochloride

A mixture of lithium7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate(0.09578 g, 0.2933 mmol) and NMP (1.5 mL) were warmed to provide ahomogeneous solution and then cooled to ambient temperature.2,4,6-Trichlorobenzoyl chloride (0.04277 mL, 0.2737 mmol) was added andthe mixture stirred at ambient temperature for 0.5 hours. Methyl3-((4-amino-1H-indazol-1-yl)methyl)benzoate (0.055 g, 0.1955 mmol) wasadded as a NMP solution (1.5 mL) and the mixture was heated to 80° C.and stirred for 4 hours. The mixture was dissolved in MeOH andconcentrated. The residue was dissolved in saturated aqueous NaHCO₃ andEtOAc and the organic layer was washed with brine and dried over Na₂SO₄.The crude material was purified by column chromatography (15%MeOH/CH₂Cl₂ adding 1% 7N NH₃/MeOH) to provide methyl3-((4-(7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)benzoateas the free base. This material was dissolved in MeOH (3.0 mL) and CHCl₃(1.0 mL), and HCl (1.955 mL, 3.910 mmol, 2.0M Et₂O) was added and themixture was stirred for 2 hours and then concentrated. The resultingsolid was washed with Et₂O and then with hexanes, and dried under vacuumto afford 0.085 g (64%) of the title compound. MS (ES+APCI) m/z=568(M+H−2HCl).

Example 97N-(1-(3-(dimethylcarbamoyl)benzyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamidedihydrochloride

Step A: Preparation of 3-(chloromethyl)-N,N-dimethylbenzamide

A solution of dimethylamine (2.91 mL, 5.82 mmol, 2.0M THF), NEt₃ (0.885mL, 6.35 mmol) and CH₂Cl₂ 30 mL was cooled to 0° C.3-(Chloromethyl)benzoyl chloride (1.0 g, 5.29 mmol) was added as aCH₂Cl₂ solution (3 mL) and the solution was stirred at 0° C. for 2 hoursand then at ambient temperature for 2 hours. The reaction was washedwith 1N HCl followed by brine, and the organic layer was dried overNa₂SO₄, filtered and concentrated. The product was purified by columnchromatography (EtOAc) to provide 0.745 g (71%) of the product ascolorless oil.

Step B: Preparation of3-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)-N,N-dimethylbenzamide

To a flask was added 3-iodo-4-nitro-1H-indazole (0.500 g, 1.73 mmol) andCH₃CN (6 mL) followed by 2-tert-butyl-1,1,3,3-tetramethylguanidine(0.523 ml, 2.59 mmol). The mixture was stirred for 5 minutes, and then3-(chloromethyl)-N,N-dimethylbenzamide (0.479 g, 2.42 mmol) was added asa CH₃CN (4 mL) solution. The reaction was stirred at ambient temperaturefor 5 hours. The mixture was concentrated and diluted with saturatedaqueous NH₄Cl (20 mL) and EtOAc (60 mL). The layers were mixed andseparated and the organic phase was washed with brine, dried overNa₂SO₄, filtered and concentrated. The crude product was purified bycolumn chromatography (EtOAc) to provide 0.567 g (72%) of the desiredproduct as an orange foam.

Step C: Preparation of3-((4-amino-1H-indazol-1-yl)methyl)-N,N-dimethylbenzamide

A solution of3-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)-N,N-dimethylbenzamide (0.400g, 0.888 mmol) and MeOH (8.8 mL) was cooled to 0° C. Zinc dust (0.290 g,4.44 mmol) was added and the mixture was stirred vigorously for 15minutes, followed by the dropwise addition of saturated aqueous NH₄Cl (9mL). The mixture was stirred vigorously for 15 minutes at 0° C. and thenwarmed to ambient temperature and stirred for an additional 1 hour. Themixture was diluted with MeOH and filtered. To the filtrate was addedsaturated aqueous NH₄OAc and the mixture was concentrated to remove bulkMeOH. The mixture was extracted with EtOAc and the combined organicextracts were washed with saturated aqueous NaHCO₃ and brine, dried overNa₂SO₄, filtered and concentrated. The crude product was purified bycolumn chromatography (2 to 20% IPA/CHCl₃) to afford 0.160 g (61%) ofthe title compound as a yellow/orange solid.

Step D: Preparation ofN-(1-(3-(dimethylcarbamoyl)benzyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamidedihydrochloride

A solution of 3-((4-amino-1H-indazol-1-yl)methyl)-N,N-dimethylbenzamide(0.15 g, 0.51 mmol) and THF (1.0 mL) was cooled to −5° C. in anice/brine bath, then LHMDS (0.48 ml, 0.48 mmol, 1.0M THF) was addeddrop-wise and the mixture was stirred for 10 minutes, during which adark emulsion formed. Ethyl7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate(Preparation A; 0.080 g, 0.24 mmol) was added dropwise as a THF solution(1.0 mL). The reaction was stirred at −5 to 0° C. for 1 hour, thenquenched with saturated aqueous NH₄Cl (10 mL). The mixture was extractedwith CH₂Cl₂ and the combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated. The crude residue wasslurried in Et₂O with vigorous stirring and then filtered through anylon filter providing crude product with >90% purity (0.083 g). Thecrude product was purified by column chromatography (5 to 20%MeOH/CH₂Cl₂ using 5% NH₄OH/MeOH). The fractions were concentrated andthe product dissolved in CH₂Cl₂ and then filtered. The filtrate wasconcentrated to provideN-(1-(3-(dimethylcarbamoyl)benzyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamideas a pale orange solid (0.060 g). This product was dissolved in MeOH(2.4 mL) and then HCl (2.41 mL, 4.81 mmol, 2.0M Et₂O) was added. Themixture was stirred for 2 hours and then concentrated. The resultingsolid was washed with Et₂O and hexanes and dried under vacuum to provide0.050 g (31%) of the title product as a pale brown powder. MS (ES+APCI)m/z=581 (M+H−2HCl).

Example 987-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-(3-(trifluoromethyl)benzyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamidedihydrochloride

Step A: Preparation of3-iodo-4-nitro-1-(3-(trifluoromethyl)benzyl)-1H-indazole

To a slurry of 3-iodo-4-nitro-1H-indazole (0.410 g, 1.42 mmol) and CH₃CN(7.0 mL) was added 1-(bromomethyl)-3-(trifluoromethyl)benzene (0.261 mL,1.70 mmol) and the solution was cooled to 0° C.2-tert-Butyl-1,1,3,3-tetramethylguanidine (0.372 mL, 1.84 mmol) wasadded and the mixture was gradually warmed to ambient temperature whereit stirred for 2 hours. The mixture was concentrated and diluted withsaturated aqueous NH₄Cl (20 mL) and EtOAc (75 mL). The layers were mixedand separated and the organic phase was washed with brine, dried overNa₂SO₄, filtered and concentrated. The crude product was passed througha silica gel plug eluting with 20% EtOAc/hexane to provide 0.542 g (85%)of the product as dark yellow/orange oil.

Step B: Preparation of 1-(3-(trifluoromethyl)benzyl)-1H-indazol-4-amine

To a round bottom flask was added3-iodo-4-nitro-1-(3-(trifluoromethyl)benzyl)-1H-indazole (0.540 g, 1.21mmol) and MeOH (12 mL). Zinc dust (0.395 g, 6.04 mmol) was addedfollowed by saturated aqueous NH₄Cl (12 mL). The mixture was stirredvigorously at ambient temperature for 2 hours. The reaction mixture wasfiltered and the solids were washed with EtOAc (30 mL). Saturatedaqueous NH₄OAc (25 mL) was added to the filtrate and the mixture wasconcentrated to remove organic solvents. The aqueous phase was thenextracted with EtOAc (3×20 mL). The combined organic extracts werewashed with a saturated aqueous NaHCO₃ solution and brine, dried overNa₂SO₄, filtered and concentrated. The crude residue was purified by 1mm preparative TLC using 5% MeOH/CH₂Cl₂ to afford 0.120 g (34%) of theproduct as a dark yellow/orange oil.

Step C: Preparation of7-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-(3-(trifluoromethyl)benzyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamidedihydrochloride

To a solution of 1-(3-(trifluoromethyl)benzyl)-H-indazol-4-amine (0.053g, 0.18 mmol) in THF (1.1 mL) was cooled to −10° C. in an ice/salt bath.LiHMDS (0.19 mL, 0.19 mmol, 1.0M THF) was added and the mixture wasstirred for 15 minutes. To this dark solution was added a THF (1.1 mL)solution of ethyl7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate(Preparation A; 0.030 g, 0.090 mmol). The mixture was slowly warmed to0° C. where it stirred for 3 hours. The reaction was quenched withsaturated aqueous NaHCO₃ and extracted with CHCl₃. The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by preparative TLC (1 mm,10% MeOH/CH₂Cl₂ adding 1% NH₃ (7N MeOH) to afford 0.026 g of the titlecompound as the freebase as a tan solid. The solid was slurried in Et₂Oand filtered, and the solid was washed with Et₂O and hexanes. Thematerial was dissolved in MeOH (2.0 mL), and HCl (0.90 mL, 1.8 mmol,2.0M Et₂O) was added. The solution was stirred for 2 hours forming awhite suspension. The mixture was filtered through a polypropylenefilter to isolate the solids. The solids were washed with Et₂O followedby hexanes and dried under vacuum to afford 0.026 g (44%) of the titlecompound as an off-white solid. MS (ES+APCI) m/z=578 (M+H−2HCl).

Example 99N-(1-(3-cyanobenzyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of3-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)benzonitrile

Prepared according to the method of Example 104, replacing3-(bromomethyl)-1-methylpyridin-2(1H)-one with3-(bromomethyl)benzonitrile.

Step B: Preparation of 3-((4-amino-1H-indazol-1-yl)methyl)benzonitrile

A slurry of 3-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)benzonitrile(0.200 g, 0.495 mmol) and MeOH (10.0 mL) was cooled to 0° C., then Zndust (0.162 g, 2.47 mmol) was added followed by saturated aqueous NH₄Cl(10 mL). The mixture was stirred at 0° C. for 1 hour, then warmed toambient temperature and stirred overnight. The mixture was diluted withMeOH and filtered. The solid was washed with CH₂Cl₂ and MeOH. To thefiltrate was added saturated aqueous NH₄OAc and the mixture wasconcentrated to remove bulk MeOH. The mixture was then extracted withEtOAc, and the combined organic extracts were washed with saturatedaqueous NaHCO₃ and brine, dried over Na₂SO₄, filtered and concentrated.The crude product was purified by column chromatography (25 to 100%EtOAc/hexane) to afford 0.090 g (73%) of the desired product as anorange oil.

Step C: Preparation ofN-(1-(3-cyanobenzyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

To a vial was added lithium7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate(0.187 g, 0.544 mmol) and NMP (3.0 mL), and the mixture was warmed untilhomogeneous and then cooled to ambient temperature.2,4,6-Trichlorobenzoyl chloride (0.0793 mL, 0.507 mmol) was added andthe dark solution was stirred at ambient temperature for 0.5 hours.3-((4-Amino-1H-indazol-1-yl)methyl)benzonitrile (0.090 g, 0.362 mmol)was added as a NMP solution (3.0 mL) and the mixture was heated to 75°C. with stirring for 3 hours. The reaction was equilibrated to ambienttemperature and the mixture was diluted with EtOAc (30 mL) and saturatedaqueous NaHCO₃ (10 mL). The organic layer was washed with brine, driedover Na₂SO₄, concentrated and purified by column chromatography (15%MeOH/CH₂Cl₂ adding 1% 7N NH₃/MeOH). The red/brown solid was slurried inEt₂O and then filtered, and the isolated solid was washed with Et₂Oproviding a pale red/brown solid that was dried under vacuum to provide0.095 g (42%) of the desired product. MS (ES+APCI) m/z=535 (M+H).

Example 100N-(5-chloro-1-(3-(trifluoromethyl)benzyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of5-chloro-1-(3-(trifluoromethyl)benzyl)-1H-indazol-4-amine

A solution of 1-(3-(trifluoromethyl)benzyl)-1H-indazol-4-amine (0.056 g,0.192 mmol) in THF (1.0 mL) was cooled to −78° C. under N₂. H₂SO₄(0.00512 mL, 0.0961 mmol) was added and the mixture was stirred for 5minutes. N-chlorosuccinimide (0.0257 g, 0.192 mmol) was added in oneportion and the reaction was stirred at −78° C. for 1 hour. Sodiumcarbonate (0.0204 g, 0.192 mmol) was added and the mixture was warmed toambient temperature. The mixture was diluted with water (5 mL) andextracted with EtOAc (3×10 mL). The combined organic layers were thenwashed with brine and dried over Na₂SO₄, filtered and concentrated. Thecrude product was purified by preparative TLC (40% EtOAc/hexane) inwhich two major bands were observed. The higher band was determined tobe the title compound (0.028 g, 44%) and was isolated as a darkyellow/green solid.

Step B: Preparation ofN-(5-chloro-1-(3-(trifluoromethyl)benzyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

A solution of 5-chloro-1-(3-(trifluoromethyl)benzyl)-1H-indazol-4-amine(0.024 g, 0.074 mmol) in THF (0.750 mL) was cooled to −10° C. and LHMDS(0.096 mL, 0.096 mmol) was added. The mixture was stirred for 15minutes, and ethyl7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate(Preparation A; 0.049 g, 0.15 mmol) was added as a THF solution (0.750mL). The mixture was slowly warmed to 0° C. where it stirred for 3hours. The reaction was quenched with saturated aqueous NaHCO₃ andextracted with CH₂Cl₂. The combined organic extracts were washed withbrine and dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified by preparative TLC (1 mm, 10% MeOH/CH₂Cl₂ with 1%NH₃ (7N MeOH)). The resulting solid was slurried in Et₂O and filteredand the solid washed with Et₂O and then finally with hexanes to providethe title compound (0.002 g, 4%) as a tan powder. MS (ES+APCI) m/z=612(M).

Example 101N-(7-chloro-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamidetrihydrochloride

Step A: Preparation of1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine

A solution of3-iodo-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (1.00 g,2.54 mmol) in MeOH (25 mL) was cooled to 0° C. Zinc dust (0.829 g, 12.7mmol) was added and the mixture was stirred for 10 minutes. Saturatedaqueous NH₄Cl was added (25 mL) and the mixture was stirred vigorouslyfor 2 hours at 0° C., then warmed to ambient temperature and stirred foran additional 2 hours. Additional saturated aqueous NH₄Cl was added(12.5 mL) and the mixture was stirred at ambient temperature for anadditional 2 hours. The mixture was diluted with MeOH and filtered. Tothe filtrate was added saturated aqueous NH₄OAc and the mixture wasconcentrated to remove bulk MeOH. The mixture was extracted with EtOAcand the combined organic extracts were washed with saturated aqueousNaHCO₃ and brine, dried over Na₂SO₄, filtered and concentrated. Theproduct was purified by column chromatography (2 to 20% IPA/CHC₁₃) toafford 0.428 g (70%) of the product as an orange solid.

Step B: Preparation of7-chloro-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine

A solution of 1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (0.390g, 1.64 mmol) and THF (8.0 mL) was cooled to −78° C. under N₂. H₂SO₄(0.0436 mL, 0.818 mmol) was added and the resulting brown suspension wasstirred for 5 minutes. N-chlorosuccinimide (0.219 g, 1.64 mmol) wasadded in one portion and the reaction was stirred at −78° C. for 1 hour.Sodium carbonate (0.173 g, 1.64 mmol) was added and the mixture waswarmed to ambient temperature. The mixture was diluted with water (20mL) and extracted with EtOAc. The combined organic layers were washedwith brine and dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified by column chromatography (5 to 30% EtOH/hexanes).The desired product was found in the lower band from the column but itwas contaminated with succinimide, so the product was dissolved in 0.5NHCl and extracted with CHCl3. The aqueous phase was basified with NaHCO3and extracted with EtOAc. The EtOAc was washed with brine, dried overNa₂SO₄, filtered and concentrated providing the title compound as a paleorange solid (0.150 g, 33%).

Step C: Preparation ofN-(7-chloro-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamidetrihydrochloride

A vial containing lithium7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate(0.171 g, 0.550 mmol) and NMP (3.0 mL) was warmed to provide ahomogeneous solution and then cooled to ambient temperature.2,4,6-Trichlorobenzoyl chloride (0.0803 mL, 0.513 mmol) was added andthe dark solution was stirred at ambient temperature for 0.5 hours.7-Chloro-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (0.100 g,0.367 mmol) was added as a NMP (3.0 mL) solution and the mixture washeated to 80° C. with stirring overnight. The reaction was equilibratedto ambient temperature and the mixture was diluted with EtOAc (30 mL)and saturated aqueous NaHCO₃ (10 mL). The organic layer was washed withbrine, dried over Na₂SO₄, filtered and concentrated. The crude productwas purified by column chromatography (15% IPA/CHCl₃ adding 1% 7NNH₃/MeOH) to provideN-(7-chloro-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide.This product was dissolved in MeOH (4.0 mL) and CH₂Cl₂ (1.0 mL), and HCl(3.67 mL, 7.33 mmol, 2.0M Et₂O) was added. The mixture was stirred for 2hours and then concentrated. The resulting solid was then washed withEt₂O and finally with hexanes and dried under vacuum overnight toprovide 0.140 g (50%) of the title compound. MS (ES+APCI) m/z=559(M+H−3HCl).

Example 1027-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-(pyridin-3-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamidetrihydrochloride

Step A: Preparation of 3-iodo-4-nitro-1-(pyridin-3-ylmethyl)-1H-indazole

To a flask was added 3-iodo-4-nitro-1H-indazole (0.300 g, 1.04 mmol) and4-(bromomethyl)pyridine hydrobromide (0.315 g, 1.25 mmol) which wereslurried in CH₃CN (5.0 mL). 2-tert-Butyl-1,1,3,3-tetramethylguanidine(0.460 mL, 2.28 mmol) was added and the mixture was stirred overnight.The mixture was diluted with water (20 mL) and stirred for 15 minutesand filtered. The collected solids were washed with water followed byEt₂O and hexanes, and dried under vacuum to provide the title compoundas a brown powder (0.304 g, 71%), which was used directly in thesubsequent step.

Step B: Preparation of 1-(pyridin-3-ylmethyl)-1H-indazol-4-amine

To a vial containing 3-iodo-4-nitro-1-(pyridin-3-ylmethyl)-1H-indazole(0.145 g, 0.381 mmol) was added THF (2.4 mL) and MeOH (1.2 mL). To thissolution was added Zn dust (0.249 g, 3.81 mmol) followed by HCl (2.54mL, 7.63 mmol, 3.0 M aqueous). The mixture was stirred for 1.0 hours.The mixture was filtered through GF/F paper and the collected solidswere washed with CHCl₃ (30 mL). A saturated aqueous KOAc solution wasadded to the filtrate until the pH was neutral and then a saturatedaqueous Rochelle's Salt solution was added. The mixture was stirredvigorously, the layers were separated and the aqueous phase wasextracted with CHCl₃. The combined organic extracts were washed withbrine and dried over Na₂SO₄, filtered and concentrated. The product waspurified by column chromatography (1 to 10% MeOH/CH₂Cl₂) to afford theproduct as a thick oil (0.041 g, 47%).

Step C: Preparation of7-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-(pyridin-3-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamidetrihydrochloride

A solution of 1-(pyridin-3-ylmethyl)-1H-indazol-4-amine (0.040 g, 0.18mmol) in THF (1.1 mL) was cooled to −10° C. in an ice/salt bath. LHMDS(0.19 mL, 0.19 mmol, 1.0M THF) was added and the mixture was stirred for15 minutes. To this dark solution was added a THF (1.1 mL) solution ofethyl7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate(Preparation A; 0.030 g, 0.090 mmol) at 0° C. The mixture was slowlywarmed to 0° C. where it stirred for 3 hours. The reaction was quenchedwith a saturated aqueous NaHCO₃ solution and extracted with CH₂Cl₂. Thecombined organic extracts were washed with brine and dried over Na₂SO₄,filtered and concentrated. The crude product was purified by preparativeTLC (1 mm, 15% MeOH/CH₂Cl₂ with NH₃) to afford 0.028 g of7-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-(pyridin-3-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideas a tan powder. This material was suspended in MeOH (4.0 mL) and HCl(0.90 mL, 1.8 mmol, 2.0M Et₂O) was added. The resulting suspension wasstirred for 3 hours and then concentrated. The solid was slurried inEt₂O and isolated by vacuum filtration. The solid was dried under vacuumovernight to afford 0.035 g of the title compound (62%). MS (ES+APCI)m/z=511 (M+H−3HCl).

Example 1037-(2-(4-Methylpiperazin-1-yl)ethoxy)-N-(1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamidetrihydrochloride

Step A: Preparation of 2-(chloromethyl)-5-(trifluoromethyl)pyridinehydrochloride

A solution of (5-(trifluoromethyl)pyridin-2-yl)methanol (0.400 g, 2.26mmol) in CH₂Cl₂ (4.4 mL) was cooled to 0° C. and SOCl₂ (0.494 mL, 6.77mmol) was added as a CH₂Cl₂ solution (2.2 mL). The reaction was allowedto gradually warm to ambient temperature over 1 hour and then stirredfor an additional 1 hour. The reaction was concentrated and dried undervacuum to provide the desired product (0.520 g, 99%) as dark oil thatwas used directly in the subsequent step.

Step B: Preparation of3-iodo-4-nitro-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazole

To a round bottom flask was added 3-iodo-4-nitro-1H-indazole (0.580 g,2.01 mmol) and CH₃CN (10 mL). 2-tert-Butyl-1,1,3,3-tetramethylguanidine(0.890 mL, 4.41 mmol) was added and the mixture was stirred for 5minutes. 2-(Chloromethyl)-5-(trifluoromethyl)pyridine hydrochloride(0.512 g, 2.21 mmol) was added as a CH₃CN solution (4 mL) and themixture was stirred at ambient temperature overnight. The mixture wasconcentrated and diluted with saturated aqueous NH₄Cl (20 mL) and EtOAc(60 mL). The layers were mixed and separated and the organic phase waswashed with brine, dried over Na₂SO₄, filtered and concentrated. Thecrude product was purified by column chromatography (50% EtOAc/hexane)to provide 0.490 g (54%) of the product as an orange solid.

Step C: Preparation of1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-amine

To a solution of3-iodo-4-nitro-1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazole(0.464 g, 1.04 mmol) in MeOH (10 mL) at 0° C. was added Zn dust (0.339g, 5.18 mmol) followed by saturated aqueous NH₄Cl (10 mL). The mixturewas stirred at 0° C. for 1 hour, then warmed to ambient temperature andstirred for an additional 1 hour. The mixture was diluted with MeOH andfiltered. Saturated aqueous NH₄OAc was added to the filtrate and themixture was concentrated to remove bulk MeOH. The mixture was extractedwith EtOAc, and the combined organic extracts were washed with saturatedaqueous NaHCO₃ and brine, dried over Na₂SO₄, filtered and concentrated.The product was purified by column chromatography (25 to 100%EtOAc/hexane) to afford 0.230 g (76%) of the product as yellow/orangeoil.

Step D: Preparation of7-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamidetrihydrochloride

To a solution of7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylicacid lithium chloride (0.0653 g, 0.188 mmol) in dry DMA (2.0 mL) at 0°C. was added POCl3 (0.0345 mL, 0.376 mmol) and the mixture was stirredat 0° C. for 30 minutes.1-((5-(Trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-amine (0.055 g,0.188 mmol) was added as a DMA solution (1.0 mL) and the mixture wasgradually warmed to ambient temperature and stirred overnight. Themixture was concentrated under vacuum and 2M LiOH (2.5 mL) was added.The mixture was stirred for 10 minutes. The mixture was diluted withCHCl₃ (20 mL) and with saturated aqueous NaHCO₃ and the layers weremixed and separated. The aqueous phase was further extracted with CHCl₃and the combined organic layers were washed with brine and dried overNa₂SO₄, filtered and concentrated. The product was purified bypreparative TLC (15% MeOH/CH₂C₁₂ adding 1% 7N NH₃/MeOH) to provide7-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamideas a tan solid (0.028 g). The solid was dissolved in MeOH (2.0 mL) andHCl (1.88 mL, 3.76 mmol, 2.0M in Et₂O) was added. The mixture wasstirred for 2 hours and then concentrated. The resulting solid waswashed with Et₂O and finally with hexanes and dried under vacuum toprovide the title compound (0.032 g, 24%). MS (ES+APCI) m/z=579(M+H−3HCl).

Example 104N-(1-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamidedihydrochloride

Step A: Preparation of 3-(bromomethyl)-1-methylpyridin-2(1H)-one

1,3-Dimethylpyridin-2(1H)-one (0.54 g, 4.4 mmol) was added to CCl₄ (100mL). N-Bromosuccinimide (0.78 g, 4.4 mmol) and benzoyl peroxide (0.11 g,0.44 mmol) were added and the reaction mixture was refluxed for 3 hours.The reaction was cooled, filtered and concentrated. The residue wassuspended in Et₂O (10 mL) and filtered to provide3-(bromomethyl)-1-methylpyridin-2(1H)-one (0.29 g, 32% yield) as asolid.

Step B: Preparation of3-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)-1-methylpyridin-2(1H)-one

3-Iodo-4-nitro-1H-indazole (0.38 g, 1.3 mmol) was reacted with K₂CO₃(0.36 g, 2.6 mmol) in DMF (4 mL) for 15 minutes.3-(Bromomethyl)-1-methylpyridin-2(1H)-one (0.28 g, 1.4 mmol) was addedand the reaction mixture was stirred overnight. The reaction mixture wasdiluted with CH₂Cl₂ (30 mL), filtered and concentrated. The residue waspartitioned between CHCl₃ and saturated aqueous NaHCO₃. The organiclayer was dried over MgSO₄ and concentrated. The residue was suspendedin EtOAc (8 mL), stirred for 20 minutes and then filtered to provide3-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)-1-methylpyridin-2(1H)-one(0.27 g, 50% yield) as a solid.

Step C: Preparation of3-((4-amino-1H-indazol-1-yl)methyl)-1-methylpyridin-2(1H)-one

3-((3-Iodo-4-nitro-1H-indazol-1-yl)methyl)-1-methylpyridin-2(1H)-one(0.26 g, 0.63 mmol) was added to MeOH (6 mL) and cooled to 0° C. Zinc(0.21 g, 3.2 mmol) was added to the reaction mixture. Saturated aqueousNH₄Cl (6 mL) was added drop-wise and the reaction mixture was stirredfor 90 minutes at ambient temperature. The reaction was diluted withMeOH (50 mL), stirred for 5 minutes and filtered. The filtrate wasdiluted with saturated NH₄OAc and the MeOH was removed under vacuum. Theaqueous mixture was extracted with CHCl₃. The organic layer was washedwith brine, dried over MgSO₄ and concentrated to provide3-((4-amino-1H-indazol-1-yl)methyl)-1-methylpyridin-2(1H)-one (0.12 g,71% yield) as a solid.

Step D: Preparation ofN-(1-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamidedihydrochloride

7-(2-(4-Methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylicacid (0.072 g, 0.21 mmol) was added to DMA (1 mL) and cooled to 0° C.Phosphorus oxychloride (0.038 mL, 0.41 mmol) was added and the reactionmixture was stirred for 30 minutes.3-((4-Amino-1H-indazol-1-yl)methyl)-1-methylpyridin-2(1H)-one (0.035 g,0.14 mmol) was added and the reaction mixture was stirred at ambienttemperature overnight. The reaction was concentrated and then suspendedin 2 M LiOH (2 mL). The resulting mixture was stirred for 30 minutes andthen diluted with CHCl3 and saturated aqueous NaHCO₃. The layers wereseparated and the aqueous phase was extracted with CHCl₃. The combinedorganic layers were dried over MgSO₄ and concentrated. The residue waspurified by preparative thin layer chromatography (1:6 2.3 M NH₃ inMeOH:CH₂Cl₂), added to MeOH (2 mL) and reacted with HCl (2 M in Et₂O, 2mL). The mixture was stirred for 60 minutes and then concentrated. Theresulting solids were suspended in Et₂O and filtered to provideN-(1-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamidedihydrochloride (0.035 g, 41% yield) as a solid. MS (ES+APCI) m/z=541(M+H−2HCl).

Example 105N-(1-((6-ethoxypyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 104, replacing3-(bromomethyl)-1-methylpyridin-2(1H)-one with1-(bromomethyl)-3-methoxybenzene. MS (ES+APCI) m/z=555 (M+H).

Example 106N-(1-((1-methyl-1H-imidazol-4-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamidedihydrochloride

Prepared according to the method of Example 104, replacing3-(bromomethyl)-1-methylpyridin-2(1H)-one with4-(chloromethyl)-1-methyl-1H-imidazole hydrochloride. MS (ES+APCI)m/z=514 (M+H).

Example 1077-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-(2-(pyridin-2-yl)ethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of3-iodo-4-nitro-1-(2-(pyridin-2-yl)ethyl)-1H-indazole

2-Tert-butyl-1,1,3,3-tetramethyl-guanidine (0.48 mL, 2.4 mmol) was addedto a mixture of 3-iodo-4-nitro-1H-indazole (0.30 g, 1.0 mmol) and2-(2-bromoethyl)pyridine hydrobromide (0.30 g, 1.1 mmol) in CH₃CN (4mL). The mixture was stirred at ambient temperature overnight, dilutedwith H₂O (35 mL), stirred for 30 minutes, and then extracted with CHCl₃.The combined organic extracts were dried over MgSO₄ and concentrated.The residue was purified by silica gel chromatography, eluting withEtOAc, to provide 3-iodo-4-nitro-1-(2-(pyridin-2-yl)ethyl)-1H-indazole(0.14 mg, 34%) as a solid.

Step B:7-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-(2-(pyridin-2-yl)ethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamidedihydrochloride

Prepared according to Example 104, Steps C-E, replacing3-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)-1-methylpyridin-2(1H)-onewith 3-iodo-4-nitro-1-(2-(pyridin-2-yl)ethyl)-1H-indazole. MS (ES+APCI)m/z=525 (M+H).

Example 108N-(1-((1H-benzo[d]imidazol-5-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamidedihydrochloride

Prepared according to the method of Example 104, replacing3-(bromomethyl)-1-methylpyridin-2(1H)-one with a mixture of tert-butyl5-(bromomethyl)-1H-benzo[d]imidazole-1-carboxylate and tert-butyl6-(bromomethyl)-1H-benzo[d]imidazole-1-carboxylate. MS (ES+APCI) m/z=550(M+H).

Example 109N-(1-(2,4-difluorobenzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: 1-(2,4-difluorobenzyl)-4-nitro-1H-indazole

To a solution of 4-nitro-1H-indazole (0.200 g, 1.226 mmol) in acetone (3mL) cooled to 0° C., was added KOH (0.103 g, 1.839 mmol). After 15minutes at 0° C., 1-(bromomethyl)-2,4-difluorobenzene (0.173 mL, 1.349mmol) was added. The mixture was allowed to stir at ambient temperatureovernight, concentrated and the residue purified on silica gel (5-25%EtOAc in hexanes) to provide 1-(2,4-difluorobenzyl)-4-nitro-1H-indazole(0.142 g, 40% yield) as a pale yellow solid.

Step B: 1-(2,4-difluorobenzyl)-1H-indazol-4-amine

A solution of 1-(2,4-difluorobenzyl)-4-nitro-1H-indazole (0.142 g, 0.491mmol), ammonium chloride (0.013 g, 0.245 mmol) in 4:1 v/v EtOH/water (5mL) was treated with iron (0.274 g, 4.91 mmol) and refluxed for 2 hours.The mixture was concentrated and the residue taken in EtOAc/water,filtered through glass fiber filter paper and concentrated again toprovide 1-(2,4-difluorobenzyl)-1H-indazol-4-amine (0.096 mg, 75% yield)as an amber oil.

Step C:N-(1-(2,4-difluorobenzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide

7-(2-Methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (0.070 g,0.296 mmol) and a 2M solution of oxalyl chloride in methylene chloride(0.163 mL, 0.326 mmol) were suspended in methylene chloride (2 mL) witha catalytic amount of DMF. The mixture was stirred for a few minutes andthen treated with 1-(2,4-difluorobenzyl)-1H-indazol-4-amine (0.084 g,0.326 mmol) as a solution in about 1 mL methylene chloride, followed byaddition of diisopropylethylamine (0.062 mL, 0.356 mmol). After stirringthe mixture overnight, the residue was shaken in water/methylenechloride and suspended solids collected by filtration to provideN-(1-(2,4-difluorobenzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide(0.070 g, 50% yield). MS (APCI) m/z=478 (M+H).

Example 110N-(1-(cyclopropylmethyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 109, replacing1-(2,4-difluorobenzyl)-1H-indazol-4-amine in Step C with1-(cyclopropylmethyl)-1H-indazol-4-amine. MS (APCI) m/z=406 (M+H).

Example 1117-(2-methoxyethoxy)-N-(1-(pyridin-4-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 109, replacing1-(2,4-difluorobenzyl)-1H-indazol-4-amine in Step C with1-(pyridin-4-ylmethyl)-1H-indazol-4-amine. MS (APCI) m/z=443 (M+H).

Example 1127-(2-methoxyethoxy)-N-(1-(pyridin-2-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 109, replacing1-(2,4-difluorobenzyl)-1H-indazol-4-amine in Step C with1-(pyridin-2-ylmethyl)-1H-indazol-4-amine. MS (APCI) m/z=443 (M+H).

Example 1137-(2-methoxyethoxy)-N-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 109, replacing1-(2,4-difluorobenzyl)-1H-indazol-4-amine in Step C with1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazol-4-amine. MS (APCI)m/z=450 (M+H).

Example 114N-(1-(4-methoxybenzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 109, replacing1-(2,4-difluorobenzyl)-1H-indazol-4-amine in Step C with1-(4-methoxybenzyl)-1H-indazol-4-amine. MS (APCI) m/z=472 (M+H).

Example 115N-(1-(cyclohexylmethyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 109, replacing1-(2,4-difluorobenzyl)-1H-indazol-4-amine in Step C with1-(cyclohexylmethyl)-1H-indazol-4-amine. MS (APCI) m/z=448 (M+H).

Example 116 tert-butyl3-((4-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate

Prepared according to the method of Example 109, replacing1-(2,4-difluorobenzyl)-1H-indazol-4-amine in Step C with tert-butyl3-((4-amino-1H-indazol-1-yl)methyl)piperidine-1-carboxylate. MS (APCI)m/z=549 (M+H).

Example 117 (R)-tert-butyl3-((4-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate

Prepared according to the method of Example 109, replacing1-(2,4-difluorobenzyl)-1H-indazol-4-amine in Step C with (R)-tert-butyl3-((4-amino-1H-indazol-1-yl)methyl)piperidine-1-carboxylate. MS (APCI)m/z=549 (M+H).

Example 1187-(2-methoxyethoxy)-N-(1-((2-methylpyridin-3-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 109, replacing1-(2,4-difluorobenzyl)-1H-indazol-4-amine in Step C with1-((2-methylpyridin-3-yl)methyl)-1H-indazol-4-amine. MS (APCI) m/z=457(M+H).

Example 119N-(1-(3-(benzyloxy)benzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 109, replacing1-(2,4-difluorobenzyl)-1H-indazol-4-amine in Step C with1-(3-(benzyloxy)benzyl)-1H-indazol-4-amine. MS (APCI) m/z=548 (M+H).

Example 1207-(2-methoxyethoxy)-N-(1-(4-(trifluoromethyl)benzyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 109, replacing1-(2,4-difluorobenzyl)-1H-indazol-4-amine with1-(4-(trifluoromethyl)benzyl)-1H-indazol-4-amine. MS (APCI) m/z=510(M+H).

Example 1217-(2-methoxyethoxy)-N-(1-(pyridin-3-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 109, replacing1-(2,4-difluorobenzyl)-1H-indazol-4-amine in Step C with1-(pyridin-3-ylmethyl)-1H-indazol-4-amine. MS (APCI) m/z=443 (M+H).

Example 122 tert-butyl4-((4-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate

Prepared according to the method of Example 109, replacing1-(2,4-difluorobenzyl)-1H-indazol-4-amine in Step C with tert-butyl4-((4-amino-1H-indazol-1-yl)methyl)piperidine-1-carboxylate. MS (APCI)m/z=549 (M+H).

Example 123 tert-butyl2-((4-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)morpholine-4-carboxylate

Prepared according to the method of Example 109, replacing1-(2,4-difluorobenzyl)-1H-indazol-4-amine in Step C with tert-butyl2-((4-amino-1H-indazol-1-yl)methyl)morpholine-4-carboxylate. MS (APCI)m/z=551 (M+H).

Example 1247-(2-methoxyethoxy)-N-(1-((6-methylpyridin-3-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 109, replacing1-(2,4-difluorobenzyl)-1H-indazol-4-amine in Step C with1-((6-methylpyridin-3-yl)methyl)-1H-indazol-4-amine. MS (APCI) m/z=457(M+H).

Example 125N-(1-benzyl-1H-indazol-4-yl)-7-methoxyimidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 109, replacing7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid and1-(2,4-difluorobenzyl)-1H-indazol-4-amine with7-methoxyimidazo[1,2-a]pyridine-3-carboxylic acid and1-benzyl-1H-indazol-4-amine, respectively. MS (APCI) m/z=398 (M+H).

Example 126N-(1-benzyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 109, replacing7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid and1-(2,4-difluorobenzyl)-1H-indazol-4-amine withimidazo[1,2-a]pyridine-3-carboxylic acid and1-benzyl-1H-indazol-4-amine, respectively. MS (APCI) m/z=368 (M+H).

Example 127N-(1-benzyl-1H-indazol-4-yl)-7-ethoxyimidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 109, replacing7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid and1-(2,4-difluorobenzyl)-1H-indazol-4-amine with7-ethoxyimidazo[1,2-a]pyridine-3-carboxylic acid and1-benzyl-1H-indazol-4-amine, respectively. MS (APCI) m/z=412 (M+H).

Example 128N-(1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 109, replacing7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid and1-(2,4-difluorobenzyl)-1H-indazol-4-amine withimidazo[1,2-a]pyridine-3-carboxylic acid and1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indazol-4-amine, respectively.MS (APCI) m/z=376 (M+H).

Example 129N-(1-(pyridin-2-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 109, replacing7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid and1-(2,4-difluorobenzyl)-1H-indazol-4-amine withimidazo[1,2-a]pyridine-3-carboxylic acid and1-(pyridin-2-ylmethyl)-1H-indazol-4-amine, respectively. MS (APCI)m/z=369 (M+H).

Example 130N-(1-(3-hydroxybenzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide

A solution ofN-(1-(3-(benzyloxy)benzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide(0.022 g, 0.040 mmol) in MeOH (2 mL) was purged with Argon, treated with10% palladium on carbon (0.002 g), purged with more Argon, and thenattached to a hydrogen balloon. The mixture was stirred at ambienttemperature overnight, filtered through glass fiber filter paper, washedwith MeOH, concentrated and the residue purified on silica gel (1-3%MeOH in DCM) to provideN-(1-(3-hydroxybenzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide(0.003 g, 18% yield) as a beige oil. MS (APCI) m/z=458 (M+H).

Example 1317-(2-methoxyethoxy)-N-(1-(piperidin-3-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamidehydrochloride

A solution of tort-butyl3-((4-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate(0.056 g, 0.10 mmol) in DCM (1 mL) was treated with 4N hydrochloric acidin dioxane (1 mL) at ambient temperature. The mixture was stirred atambient temperature overnight, concentrated to afford7-(2-methoxyethoxy)-N-(1-(piperidin-3-ylmethyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamidehydrochloride (0.0046 g, 93% yield) as a brown oil. MS (APCI) m/z=449(M+H).

Example 132N-(1-((1-acetylpiperidin-3-yl)methyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: tert-Butyl3-((4-nitro-1H-indazol-1-yl)methyl)piperidine-1-carboxylate

To a solution of 4-nitro-1H-indazole (0.200 g, 1.23 mmol) in DMA (3 mL)was added 60% sodium hydride (0.074 g, 1.84 mmol) at ambienttemperature. After 30 minutes, tert-butyl3-(tosyloxymethyl)piperidine-1-carboxylate (0.544 g, 1.47 mmol) wasadded. The mixture was heated at 100° C. overnight, diluted with water,extracted with DCM, dried (phase separator silicone treated filterpaper), concentrated and the residue purified on silica gel (10-50%EtOAc in DCM) to provide tert-butyl3-((4-nitro-1H-indazol-1-yl)methyl)piperidine-1-carboxylate (0.176 g,40% yield) as a yellow gum.

Step B: 4-Nitro-1-(piperidin-3-ylmethyl)-1H-indazole

A solution of tert-butyl3-((4-nitro-1H-indazol-1-yl)methyl)piperidine-1-carboxylate (0.118 g,0.327 mmol) in DCM (1.6 mL) was treated with trifluoroacetic acid (0.4mL) at ambient temperature and stirring continued for 2 hours. Thesolvent was concentrated and the resulting gum was dried under highvacuum to afford 4-nitro-1-(piperidin-3-ylmethyl)-1H-indazole (0.108 g,92% yield) as a brown oil.

Step C: 1-(3-((4-Nitro-1H-indazol-1-yl)methyl)piperidin-1-yl)ethanone

A solution of 4-nitro-1-(piperidin-3-ylmethyl)-1H-indazole (0.050 g,0.139 mmol), triethylamine (0.097 mL, 0.699 mmol) in DCM (1 mL) wastreated with acetic anhydride (0.0158 mL, 0.168 mmol) at ambienttemperature and stirring continued for 1 hour. The mixture was quenchedwith saturated aqueous sodium bicarbonate, extracted with DCM, dried(phase separator silicone treated filter paper) and concentrated toprovide 1-(3-((4-nitro-1H-indazol-1-yl)methyl)piperidin-1-yl)ethanone(0.022 g, 52% yield) as a yellow oil.

Step D: 1-(3-((4-Amino-1H-indazol-1-yl)methyl)piperidin-1-yl)ethanone

A solution of1-(3-((4-nitro-1H-indazol-1-yl)methyl)piperidin-1-yl)ethanone (0.022 g,0.073 mmol) in MeOH (1 mL) was purged with Argon, treated with 10%palladium on carbon (0.002 g) purged with more Argon, and then attachedto a hydrogen balloon. The mixture was stirred at ambient temperatureovernight, filtered through glass fiber filter paper, washed with MeOHand concentrated to give1-(3-((4-amino-1H-indazol-1-yl)methyl)piperidin-1-yl)ethanone (0.020 g,100% yield) as an amber oil.

Step E:N-(1-((1-acetylpiperidin-3-yl)methyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 109, replacing1-(2,4-difluorobenzyl)-1H-indazol-4-amine with1-(3-((4-amino-1H-indazol-1-yl)methyl)piperidin-1-yl)ethanone. MS (APCI)m/z=491 (M+H).

Example 1337-(2-Methoxyethoxy)-N-(1-phenyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: 4-Nitro-1-phenyl-1H-indazole

A mixture of 2,6-dinitrobenzaldehyde (0.200 g, 1.020 mmol) and phenylhydrazine (0.120 mL, 1.224 mmol) in EtOH (1.5 mL) and acetic acid (0.15mL) was stirred at ambient temperature for 2 hours. The resulting redsolution was concentrated and the red residue was dissolved in EtOH (20mL) and treated with a solution of potassium hydroxide (0.224 g, 4.0mmol) in water (2 mL). Stirring was continued at ambient temperature for2 hours. The solution was concentrated to a black solid, dissolved inEtOAc (100 mL), washed with 1N hydrochloric acid (50 mL×3), saturatedaqueous sodium bicarbonate (25 mL), brine (25 mL), dried (phaseseparator silicone treated filter paper), concentrated to a brown solidand then purified on silica gel (10-50% EtOAc in hexanes) to provide4-nitro-1-phenyl-1H-indazole (0.140 g, 57% yield) as a pale yellowsolid.

Step B: 1-Phenyl-1H-indazol-4-amine

A solution of 4-nitro-1-phenyl-1H-indazole (0.140 g, 0.585 mmol),ammonium chloride (0.016 g, 0.293 mmol) in 4:1 v/v EtOH/water (5 mL) wastreated with iron (0.327 g, 5.85 mmol) and refluxed for 2 hours. Themixture was concentrated and the residue taken in EtOAc/water, filteredthrough glass fiber filter paper and concentrated again to provide1-phenyl-1H-indazol-4-amine (0.071 g, 58% yield) as a beige solid.

Step C:7-(2-Methoxyethoxy)-N-(1-phenyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 109, replacing1-(2,4-difluorobenzyl)-1H-indazol-4-amine with1-phenyl-1H-indazol-4-amine. MS (APCI) m/z=428 (M+H).

Example 134N-(1-Benzyl-5-bromo-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: 1-Benzyl-1H-indazol-4-amine

A solution of 1-benzyl-4-nitro-1H-indazole (0.404 g, 1.595 mmol),ammonium chloride (0.043 g, 0.798 mmol) in 4:1 v/v EtOH/water (10 mL)was treated with iron (0.891 g, 15.95 mmol) and refluxed for 2 hours.The mixture was concentrated and the residue taken in EtOAc/water,filtered through glass fiber filter paper and concentrated again toprovide 1-benzyl-1H-indazol-4-amine (0.353 mg, 99% yield).

Step B: 1-Benzyl-5-bromo-1H-indazol-4-amine

A solution of 1-benzyl-1H-indazol-4-amine (0.087 g, 0.39 mmol) in DMF (2mL) was treated with N-bromosuccinimide (0.069 g, 0.39 mmol) at ambienttemperature and stirred for 4 hours. The mixture was diluted with water,extracted with EtOAc, dried (phase separator silicone treated filterpaper), concentrated and purified on silica gel (10-50% EtOAc inhexanes) to provide 1-benzyl-5-bromo-1H-indazol-4-amine (0.005 g, 4%yield).

Step C:N-(1-Benzyl-5-bromo-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 109, replacing1-(2,4-difluorobenzyl)-1H-indazol-4-amine with1-benzyl-5-bromo-1H-indazol-4-amine. MS (APCI) m/z=522 (M+2H).

Example 135N-(1-benzyl-7-chloro-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: 1-benzyl-5-chloro-1H-indazol-4-amine

A solution of 1-benzyl-1H-indazol-4-amine (0.080 g, 0.36 mmol) in DMF (2mL) was treated with N-chlorosuccinimide (0.053 g, 0.39 mmol) at ambienttemperature and stirred for 4 hours. The mixture was diluted with water,extracted with EtOAc, dried (phase separator silicone treated filterpaper), concentrated and purified on silica gel (10-50% EtOAc inhexanes) to provide 1-benzyl-5-chloro-1H-indazol-4-amine (0.035 g, 38%yield).

Step B:N-(1-benzyl-7-chloro-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 109, replacing1-(2,4-difluorobenzyl)-1H-indazol-4-amine with1-benzyl-7-chloro-1H-indazol-4-amine. MS (APCI) m/z=476 (M+H).

Example 136N-(1-benzyl-5,7-dichloro-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: 1-benzyl-5,7-dichloro-1H-indazol-4-amine

A solution of 1-benzyl-1H-indazol-4-amine (0.080 g, 0.36 mmol) in DMF (2mL) was treated with N-chlorosuccinimide (0.053 g, 0.39 mmol) at ambienttemperature and stirred for 4 hours. The mixture was diluted with water,extracted with EtOAc, dried (phase separator silicone treated filterpaper), concentrated and purified on silica gel (10-50% EtOAc inhexanes) to provide 1-benzyl-5,7-dichloro-1H-indazol-4-amine (0.008 g,9% yield).

Step B:N-(1-benzyl-5,7-dichloro-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 109, replacing1-(2,4-difluorobenzyl)-1H-indazol-4-amine with1-benzyl-5,7-dichloro-1H-indazol-4-amine. MS (APCI) m/z=510 (M+).

Example 137N-(1-benzyl-5-chloro-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: 1-Benzyl-5-chloro-1H-indazol-4-amine

A solution of 1-benzyl-1H-indazol-4-amine (0.080 g, 0.36 mmol) in DMF (2mL) was treated with N-chlorosuccinimide (0.053 g, 0.39 mmol) at ambienttemperature and stirred for 4 hours. The mixture was diluted with water,extracted with EtOAc, dried (phase separator silicone treated filterpaper), concentrated and purified on silica gel (10-50% EtOAc inhexanes) to provide 1-benzyl-5-chloro-1H-indazol-4-amine (0.035 g, 38%yield).

Step B: N-(1-benzyl-5-chloro-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 109, replacing1-(2,4-difluorobenzyl)-1H-indazol-4-amine with1-benzyl-5-chloro-1H-indazol-4-amine. MS (APCI) m/z=476 (M+).

Example 138N-(1-((6-isopropylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of ethyl 6-chloropicolinate

To 6-chloropicolinic acid (5.01 g, 31.8 mmol) in EtOH (100 mL) was addedconcentrated HCl (6 mL, 78 mmol). The reaction was heated to reflux forovernight, cooled to ambient temperature and concentrated under reducedpressure. The residue was dissolved in DCM (100 mL) and NaOH (2M)aqueous solution was added until pH=8. The aqueous layer was thenextracted with DCM. The combined organic extracts were combined, dried(Na₂SO₄) and concentrated under reduced pressure to give the desiredproduct (85%).

Step B: Preparation of ethyl 6-(prop-1-en-2-yl)picolinate

A first flask was charged with 1,4-dioxane/H₂O (50 mL/10 mL). The flaskwas cooled to 0° C. and vacuum was applied for 20 minutes. A secondflask was charged with ethyl 6-chloropicolinate (4.200 g, 22.63 mmol),potassium isopropenyltrifluoroborate (4.353 g, 29.42 mmol), K₂CO₃ (4.378g, 31.68 mmol), diacetoxypalladium (0.1524 g, 0.6789 mmol) and sodium2′-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate (0.6959 g,1.358 mmol). The flask was also evacuated with vacuum and back filledwith N₂ three times. The cold degassed dioxane/H₂O solution was added tothe second flask, which was evacuated with vacuum and back filled withargon five times. The reaction mixture was then heated to 80° C. for 3hours. The reaction was cooled to ambient temperature, filtered andconcentrated under reduced pressure. The residue was diluted with EtOAc(200 mL), washed with saturated NaHCO₃, dried (Na₂SO₄) and concentratedto give the desired product, which was used without furtherpurification.

Step C: Preparation of ethyl 6-isopropylpicolinate

To ethyl 6-(prop-1-en-2-yl)picolinate (4.63 g, 24.2 mmol) in EtOH (50mL) was added Pd/C (0.61 g, 0.573 mmol). The reaction mixture was purgedwith nitrogen and hydrogen three times each. A hydrogen balloon wasapplied to the reaction for three hours. The reaction was then purgedwith nitrogen, filtered through Celite® and washed with EtOH (100 mL).Solvent was removed under reduced pressure to give the desired product(93%).

Step D: Preparation of (6-isopropylpyridin-2-yl)methanol

To ethyl 6-isopropylpicolinate (4.63 g, 24.0 mmol) in THF (50 mL) at 0°C. was added LAH (0.909 g, 24.0 mmol). The cold bath was removed, andthe reaction mixture was stirred for 2 hours and quenched carefully withsodium sulfate decahydrate. The reaction mixture was then filteredthrough Celite® and washed with Et₂O (200 mL). The filtrate wasconcentrated under reduced pressure to give the desired product (86%).

Step E: Preparation of 2-(chloromethyl)-6-isopropylpyridinehydrochloride

To (6-isopropylpyridin-2-yl)methanol (3.13 g, 20.7 mmol) in DCM (20 mL)at 0° C. was added sulfurous dichloride (12.3 g, 104 mmol). The coldbath was removed and the reaction mixture was stirred for one hour.Solvent was removed under reduced pressure to give the desired product(98%).

Step F: Preparation of3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole

To 3-bromo-4-nitro-1H-indazole (4.91 g, 20.3 mmol) in DMF (50 mL) wasadded 2-(chloromethyl)-6-isopropylpyridine hydrochloride (4.18 g, 20.3mmol) and K₂CO₃ (8.41 g, 60.8 mmol). The reaction mixture was stirredfor 18 hours. Solvent was removed under reduced pressure. The residuewas diluted with EtOAc (100 mL). The resulting suspension was washedwith water and brine. The combined organic extracts were dried (Na₂SO₄),filtered and purified by silica gel flash chromatography (1:2EtOAc/hexanes) to give the desired product (67%).

Step G: Preparation of1-((6-isopropylpyridin-2-yl)methyl)-1H-indazol-4-amine

To 3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole (2.10g, 5.60 mmol) in EtOH (30 mL) was added Pd(OH)₂/C (1.21 g, 1.72 mmol).The reaction mixture purged with N₂ and H₂ three times each. Thereaction was then charged with H₂ to 45 psi. The reaction mixture wasstirred for 4 hours and filtered through Celite®. The Celite® was washedwith EtOH (200 mL) and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel flash chromatography(EtOAc/hexane, 2:1) to give the desired product (68%).

Step H: Preparation of 1N-(1-((6-isopropylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

To lithium7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate(188 mg, 0.595 mmol) was added NMP (5 mL, distilled over oven driedMgSO₄ directly into the 25 mL flask charged with the lithium salt). Aheat gun was used to dissolve the starting material. The flask wascooled to 0° C. and 2,4,6-trichlorobenzoyl chloride (94.2 μL, 0.590mmol) was added drop-wise. The cold bath was removed after addition wascomplete, and the reaction mixture was stirred for another hour. Thereaction mixture turned from a clear solution to slightly cloudy.1-((6-Isopropylpyridin-2-yl)methyl)-1H-indazol-4-amine (120 mg, 0.451mmol) was added in one portion to the reaction mixture and the reactionwas heated to 88° C. for 5 hours. NMP was removed by a vacuumdistillation (at the same bath temperature) until the reaction mixturebecame a thick oil. NaOH (1.8 mmol) in H₂O (10 mL) was added to thethick oil and the solution was stirred at 80° C. for 30 minutes. Thesolution was cooled to ambient temperature and the pH of the darksolution was adjusted to pH 12 to 13 with saturated NH₄Cl. The solutionwas cooled to 0° C. and H₂O (20 mL) was added. Stirring was continuedfor 30 minutes, during which time solids precipitated out of solution.The mixture was filtered and the filtrate was washed with saturatedNaHCO₃ and H₂O. The resulting solid was dissolved in DCM, dried(Na₂SO₄), filtered and concentrated. The residue was triturated withMTBE give final product (15%). MS (ES+APCI) m/z=553.1 (M+H).

Example 139N-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of ethyl1-isopropyl-5-methyl-H-pyrazole-3-carboxylate

To ethyl 2,4-dioxopentanoate (20.1 g, 127 mmol) in acetic acid (100 mL)at 0° C. was added drop-wise isopropylhydrazine (9.42 g, 127 mmol). Thecold bath was removed and the reaction mixture was stirred for 2 hours.The reaction mixture was then diluted with EtOAc/H₂O (300 mL/100 mL).The organic layer was washed with saturated NaHCO₃ aqueous solution (100mL), H₂O (50 mL) and brine (50 mL). The organic layer was dried (Na₂SO₄)and concentrated. The residue was purified by silica gel flashchromatography (1:2 EtOAc/hexane) to give the desired product (31%).

Step B: Preparation of (1-isopropyl-5-methyl-1H-pyrazol-3-yl)methanol

To ethyl 1-isopropyl-5-methyl-1H-pyrazole-3-carboxylate (7.68 g, 39.1mmol) in THF (50 mL) at 0° C. was added LAH (1.49 g, 39.1 mmol). Thecold bath was removed, and the reaction mixture was stirred for 2 hoursand quenched carefully with sodium sulfate decahydrate. The reactionmixture was filtered through Celite® and washed with Et₂O (200 mL). Thefiltrate was concentrated under reduced pressure to give the desiredproduct (88%).

Step C: Preparation of 3-(chloromethyl)-1-isopropyl-5-methyl-1H-pyrazolehydrochloride

To (1-isopropyl-5-methyl-1H-pyrazol-3-yl)methanol (5.3 g, 34 mmol) inDCM (20 mL) at 0° C. was added sulfurous dichloride (20 g, 172 mmol).The cold bath was removed and the reaction mixture was stirred for onehour. Solvent was removed under reduced pressure to give the desiredproduct (99%).

Step D: Preparation ofN-(1-((1-isopropyl-5-methyl-1H-pyrazol-3-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared from 3-(chloromethyl)-1-isopropyl-5-methyl-1H-pyrazolehydrochloride according to the method of Example 66 (Steps F to H),replacing 2-(chloromethyl)-6-isopropylpyridine hydrochloride in Step Fwith 3-(chloromethyl)-1-isopropyl-5-methyl-1H-pyrazole hydrochloride. MS(ES+APCI) m/z=556.1 (M+H).

Example 140N-(1-(3-methoxybenzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 139 from7-(methoxymethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid,3-iodo-4-nitro-1H-indazole and 1-(bromomethyl)-3-methoxybenzene. MS(ES+APCI) m/z=472.3 (M+H).

Example 141N-(1-(3-chlorobenzyl)-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 139 from7-(methoxymethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid,3-iodo-4-nitro-1H-indazole and 1-(bromomethyl)-3-chlorobenzene. MS(ES+APCI) m/z=476.2 (M+H).

Example 1427-(2-methoxyethoxy)-N-(1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 139 from7-(methoxymethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid,3-iodo-4-nitro-1H-indazole and 2-(bromomethyl)-6-methylpyridine. MS(ES+APCI) m/z=457.2 (M+H).

Example 1437-(2-methoxyethoxy)-N-(1-(3-methylbenzyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 139 from7-(methoxymethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid,3-iodo-4-nitro-1H-indazole and 1-(bromomethyl)-3-methylbenzene. MS(ES+APCI) m/z=456.3 (M+H).

Example 144N-(1-benzyl-1H-indazol-4-yl)-6-fluoroimidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of ethyl6-fluoroimidazo[1,2-a]pyridine-3-carboxylate

5-Fluoropyridine-2-amine (1 g, 8.92 mmol) and ethyl2,3-dichloro-3-oxopropanoate (39.6 g, 10.7 mmol, 5% in benzene) wereadded to a flask along with 75 mL of ethanol and stirred overnight atambient temperature. The material was purified on Silica gel usingmethanol and ethyl acetate (Rf=0.4 in 5% MeOH/ethyl acetate) to provide110 mg of the desired compound as a waxy solid, 95% pure by LC. MS(ES+APCI) m/z=209.2 (M+H).

Step B: Preparation of 6-fluoroimidazo[1,2-a]pyridine-3-carboxylic acid

Ethyl 6-fluoroimidazo[1,2-a]pyridine-3-carboxylate (0.10 g, 0.48 mmol)and lithium hydroxide monohydrate (0.020 g, 0.48 mmol) were added to amixture of water, THF and ethanol (1:2:1) and heated in a sealed vial at65° C. for 6 hours. The solvent was removed by rotary evaporation toyield 87 mg of the desired product. MS (ES+APCI) m/z=181.1 (M+H).

Step C: Preparation of 1-benzyl-4-nitro-1H-indazole

4-Nitro-1H-indazole (1.0 g, 6.13 mmol) and potassium carbonate (1.69 g,12.3 mmol) were added to DMF and stirred at room temperature overnight.Water (50 mL) was added and the product was extracted with ethyl acetateand dried over magnesium sulfate. Crude, brown solid was purified onsilica gel using hexanes/ethyl acetate. First isolated peak (730 mg) wasthe desired 1-benzyl regio-isomer, as confirmed by NMR.

Step D: Preparation of 1-benzyl-1H-indazol-4-amine

1-benzyl-4-nitro-1H-indazole (0.40 g, 1.59 mmol) in 4:1 ethanol/water(10 mL) was treated with ammonium chloride (0.043 g, 0.79 mmol),followed by Fe (0) (0.89 g, 15.95 mmol) and heated for 1 hr. A singleproduct was observed on HPLC. The solvent was removed and residue shakenin ethyl acetate and filtered through GF/F paper, and concentrated toyield 353 of orange, crude gum. MS (ES+APCI) m/z=224.3 (M+H).

Step E: Preparation ofN-(1-benzyl-1H-indazol-4-yl)-6-fluoroimidazo[1,2-a]pyridine-3-carboxamide

6-Fluoroimidazo[1,2-a]pyridine-3-carboxylic acid (0.083 g, 0.46 mmol)was added as a suspension to dichloromethane, and then oxalyl dichloride(0.28 mL, 0.55 mmol) was added slowly. The mixture was allowed to stirfor 10 minutes, then a solution of 1-benzyl-1H-indazole-4-amine (0.10 g,0.46 mmol, above, step D) and N-ethyl-isopropylpropan-2-amine (0.11 mL,0.60 mmol) were added and the reaction stirred for 2 hours. The solventwas concentrated and the resulting crude material was purified on silicagel using ethyl acetate and methanol (Rf=0.18 in 5% MeOH in ethylacetate) to provide 20 mg of the desired product. MS (ES+APCI) m/z=386.4(M+H).

Example 145N-(1-benzyl-1H-indazol-4-yl)-7-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

A dried round bottom flask equipped with a reflux condenser and anitrogen line was charged with tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(16.7 mg, 0.057 mmol),N-(1-benzyl-1H-indazol-4-yl)-7-bromoimidazo[1,2-a]pyridine-3-carboxamide(23 mg, 0.052 mmol), Pd(PPh₃)₄(3.0 mg, 0.003 mmol), and potassiumcarbonate (36 mg, 0.26 mmol). To the flask was added a water/DMF/CH₃CNmixture (1:1:4.5; 0.1:0.1:0.6 mL), and the reaction mixture was degassedunder nitrogen and heated at 80° C. for 6 hours. The cooled reactionmixture was diluted with water and the resulting suspension wasextracted with EtOAc and DCM. The combined organic extracts were driedover anhydrous sodium sulfate and concentrated to afford the crudeproduct. The crude product was subjected to preparative thin-layerchromatography on silica with 8% MeOH/DCM as eluent to afford 13.9 mg ofthe desired product as a yellow solid. MS (ES+APCI) m/z=534 (M+H)detected.

Example 1467-acetyl-N-(1-benzyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

A dried flask flushed with nitrogen was charged withN-(1-benzyl-1H-indazol-4-yl)-7-bromoimidazo[1,2-a]pyridine-3-carboxamide(150 mg, 0.34 mmol), tri-o-tolylphosphine (20 mg, 0.067 mmol),tris-dibenzylideneacetone dipalladium (0) (31 mg, 0.033 mmol), anhydrousDMF (4.5 mL) and tributyl(1-ethoxyvinyl)stannane (0.13 mL, 0.39 mmol).The resulting mixture was immediately degassed under a nitrogenatmosphere, triethylamine (0.056 mL, 0.40 mmol) was added, and the flaskwas heated at 100° C. for 6 hours. To the cooled reaction was addedconcentrated aqueous hydrochloric acid (0.5 mL) and stirring wascontinued at ambient temperature for two hours. The reaction wasquenched with excess saturated aqueous sodium bicarbonate, and theresulting suspension was extracted with EtOAc and DCM. The combinedorganic extracts were dried over anhydrous sodium sulfate andconcentrated to afford the crude product. The crude product wassubjected to preparative thin-layer chromatography on silica with 4%MeOH/DCM as eluent to afford 55 mg of desired product as an off-whitesolid. MS (ES+APCI) m/z=410 (M+H) detected.

Example 147N-(1-benzyl-1H-indazol-4-yl)-7-(1-hydroxyethyl)imidazo[1,2-a]pyridine-3-carboxamide

A solution of7-acetyl-N-(1-benzyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Example 146; 10 mg, 0.024 mmol) in a 1:1 THF/MeOH mixture (0.2 mL) wastreated at ambient temperature with excess sodium borohydride (3.7 mL,0.10 mmol), and stirring continued overnight. The reaction was quenchedwith excess saturated aqueous sodium bicarbonate and the resultingsuspension was extracted with EtOAc and DCM. The combined organicextracts were dried over anhydrous sodium sulfate, and concentrated toafford the crude product. The crude product was subjected to preparativethin-layer chromatography on silica with MeOH/DCM as eluent to afford8.8 mg of the desired product as a white solid. MS (ES+APCI) m/z=412(M+H) detected.

Example 148N-(1-benzyl-1H-indazol-4-yl)-7-(1-morpholinoethyl)imidazo[1,2-a]pyridine-3-carboxamide

To a solution of7-acetyl-N-(1-benzyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide(Example 146; 10.8 mg, 0.026 mmol) in DCM (0.6 mL) was added morpholine(3 equivalents). The resulting solution was stirred at ambienttemperature for two hours, after which sodium triacetoxyborohydride (28mg, 0.13 mmol, 5 equivalents) was added. The resulting suspension wasstirred at ambient temperature for 100 hours. The reaction was quenchedwith excess saturated aqueous sodium bicarbonate, and the resultingsuspension was extracted with EtOAc and DCM. The combined organicextracts were dried over anhydrous sodium sulfate, and concentrated toafford the crude product. The crude product was subjected to preparativethin-layer chromatography on silica with MeOH/DCM as eluent to afford0.3 mg of the desired product as a white solid. MS (ES+APCI) m/z=481(M+H) detected.

Example 1497-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-((2-methylthiazol-5-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 5-(bromomethyl)-2-methylthiazole

To a solution of (2-methylthiazol-5-yl)methanol (335 mg, 2.59 mmol) inanhydrous DMF (3 mL) were added triphenylphosphine (1.02 g, 3.89 mmol)and carbon tetrabromide (1.29 g, 3.89 mmol). The resulting mixture wasstirred at ambient temperature overnight (about 18 hours), then dilutedwith water (10 mL), and EtOAc (20 mL), and the phases separated. Theaqueous phase was extracted with EtOAc (2×25 mL), and the organicextracts were combined, dried over sodium sulfate, filtered andconcentrated. The crude product was purified by flash liquidchromatography on silica with Hexanes:EtOAc (10:1) as the eluent toprovide the desired product (0.498 mg).

Step B: Preparation of5-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)-2-methylthiazole

To a solution of 3-iodo-4-nitro-1H-indazole (441 mg, 1.53 mmol) inanhydrous DMF (3 mL) were added potassium carbonate (422 mg, 3.05 mmol),and 5-(bromomethyl)-2-methylthiazole (440 mg, 2.30 mmol) at ambienttemperature and under a nitrogen atmosphere. The resulting mixture wasstirred at ambient temperature overnight (about 18 hours). The reactionmixture was diluted with water (10 mL) and EtOAc (20 mL). The phaseswere separated and the aqueous phase was extracted with EtOAc (2×25 mL).The combined organic extracts were concentrated, and the residuesubjected to flash liquid chromatography on silica with Hexanes:EtOAc(10:1) as the eluent to afford the desired product (611 mg).

Step C: Preparation of3-iodo-1-((2-methylthiazol-5-yl)methyl)-1H-indazol-4-amine

To a solution of5-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)-2-methylthiazole (332 mg,0.830 mmol) in EtOH/water (4:1, 10 mL) was added iron powder (463 mg,8.30 mmol) and ammonium chloride (44.4 mg, 0.83 mmol). The resultingmixture was heated at 85° C. with vigorous magnetic stirring for threehours. The mixture was cooled to ambient temperature, concentrated, andEtOAc (40 mL) and triethylamine (10 mL) were added. The resultingmixture was heated at 85° C. for 20 minutes, then cooled to 45° C.,filtered through a Celite plug, and the plug was rinsed with MeOH (30mL). The combined organic filtrates were concentrated, the residue wasextracted with DCM (3×30 mL), the combined organic extracts dried oversodium sulfate, filtered and concentrated to afford the desired product(307 mg).

Step D: Preparation ofN-(3-iodo-1-((2-methylthiazol-5-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

A solution of 3-iodo-1-((2-methylthiazol-5-yl)methyl)-1H-indazol-4-amine(40 mg, 0.11 mmol) in anhydrous THF (3 mL) was treated at ambienttemperature under a nitrogen atmosphere with lithiumbis(trimethylsilyl)amide (1.0 M in THF, 0.24 mL). The resulting brownsolution was added dropwise to a cooled (ice-water) solution of ethyl7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate(35.9 mg, 0.11 mmol) in anhydrous THF (3 mL). The reaction mixture wasallowed to warm to ambient temperature, and was diluted with water (10ml). The resulting mixture was extracted thoroughly with ethyl acetateand dichloromethane. The combined organic extracts were dried oversodium sulfate, the solids removed by filtration, and the filtrate wasconcentrated to afford an oil. The crude oil was subjected topreparative thin-layer chromatography on silica with MeOH/DCM as theeluent to afford 11.6 mg of the desired product.

Step E: Preparation of7-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-((2-methylthiazol-5-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

A solution ofN-(3-iodo-1-((2-methylthiazol-5-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide(11.5 mg, 0.018 mmol) in absolute EtOH (1 mL) was treated with Pd/C(Degussa, wet, 10% wt, 2 mg), the reaction flask was flushed withhydrogen, and stirring at ambient temperature was continued for sevenhours. The reaction was diluted with DCM, the catalyst was removed byfiltration, and the filtrate concentrated to afford the crude product.The crude product was subjected to preparative thin-layer chromatographyon silica with ammonia/MeOH/DCM as eluent to afford 1.9 mg of thedesired product. MS (ES+APCI) m/z=531 (M+H) detected.

Example 1507-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine

A solution of3-iodo-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (Example 89,Steps A-B; 1.00 g, 2.54 mmol) in MeOH (25 mL) was cooled to 0° C. Zincdust (0.829 g, 12.7 mmol) was added and the mixture was stirred for 10minutes. Saturated aqueous NH₄Cl was added (25 mL) and the mixture wasstirred vigorously for 2 hours at 0° C. and then warmed to ambienttemperature and stirred for an additional 2 hours. Additional saturatedaqueous NH₄Cl was added (12.5 mL) and the mixture was stirred at ambienttemperature for an additional 2 hours. The mixture was diluted with MeOHand filtered. To the filtrate was added saturated aqueous NH₄OAc and themixture was concentrated to remove bulk MeOH. The mixture was thenextracted with EtOAc and the combined organic extracts were washed withsaturated aqueous NaHCO₃ and brine, dried over Na₂SO₄, filtered andconcentrated. The crude material was purified by column chromatography(2 to 20% IPA/CHCl₃) to afford 0.428 g (70%) of the desired product asan orange solid.

Step B: Preparation of7-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

LHMDS (1.595 mL, 1.595 mmol, 1.0M THF) was added drop-wise to a solutionof 1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (0.190 g, 0.7974mmol) in THF (4 mL) at 0° C., resulting in a dark solution. The mixturewas stirred at 0° C. for 10 minutes, then ethyl7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate(Preparation A; 0.5566 g, 1.674 mmol) was added in one portion and themixture was stirred overnight. The reaction mixture was diluted withsaturated aqueous NaHCO₃ and extracted with CH₂Cl₂. The combined organiclayers were dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified by column chromatography (5 to 20% MeOH/CH₂Cl₂using 5% NH₄OH/MeOH) to provide 0.254 g (61%) of the desired product asa pale brown powder. MS (ES+APCI) m/z=525 (M+H).

Example 1517-(2-methoxyethoxy)-N-(1-phenethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 109, replacing1-(2,4-difluorobenzyl)-1H-indazol-4-amine with1-phenethyl-1H-indazol-4-amine. MS (APCI) m/z=456 (M+H).

Example 152N-(1-benzyl-1H-indazol-4-yl)-7-cyanoimidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of ethyl 7-cyanoimidazo[1,2-a]pyridine-3-carboxylate

To 2-aminoisonicotinonitrile (4.6 g, 38.6 mmol) was added ethyl2-chloro-3-oxopropanoate (184 mL, 57.9 mmol) and EtOH (10 mL) and thereaction was heated to 75° C. for 6 hours. A precipitated solid wasremoved by vacuum filtration and was partitioned between saturatedaqueous NaHCO₃ and EtOAc. The aqueous layer was extracted with EtOAc andthe combined organic extracts were dried over Na₂SO₄ and concentrated togive 1.4 g of unreacted amino-isonicotinonitrile (30%). The filtrate wasconcentrated to give a beige solid which was also partitioned betweenEtOAc and saturated aqueous NaHCO₃. The aqueous layer was extracted withEtOAc and the combined organic extracts were dried over Na₂SO₄ andconcentrated to give 6.4 g of a beige solid. This crude material waspurified by column chromatography (30 to 50% EtOAc/hexanes) providing2.23 g (26%) of the title compound.

Step B: Preparation of 7-cyanoimidazo[1,2-a]pyridine-3-carboxylic acid

To a mixture of ethyl 7-cyanoimidazo[1,2-a]pyridine-3-carboxylate (2.23g, 10.4 mmol) in 100 mL of THF:EtOH:water (1:2:1) was added LiOH (0.248g, 10.4 mmol). The reaction mixture was stirred at ambient temperatureovernight. The reaction was concentrated and diluted with water, cooledin an ice bath and acidified to pH=3 with 1 M HCl producing a whiteprecipitate. The precipitate was removed by vacuum filtration and driedunder vacuum with a methanol azeotrope providing 1.62 g of the titlecompound as a white solid.

Step C: Preparation ofN-(1-benzyl-1H-indazol-4-yl)-7-cyanoimidazo[1,2-a]pyridine-3-carboxamide

To a solution of 7-cyanoimidazo[1,2-a]pyridine-3-carboxylic acid (0.0527g, 0.282 mmol) in 0.200 mL of CH₂Cl₂ was added a drop of DMF followed byoxalyl chloride (1.1 equivalents, 2M CH₂Cl₂). The reaction was stirredfor 5 minutes until bubbling ceased. 1-Benzyl-1H-indazol-4-amine (0.0629g, 0.282 mmol) was added as a solution in 0.600 mL of CH₂Cl₂ followed byDIEA (1.2 equivalents). The reaction was stirred at ambient temperatureovernight. The reaction was concentrated and the solids were washed withEt₂O, water, 2M Na₂CO₃, water, and finally with Et₂O again to providedthe desired product as a beige solid 0.072 g (65%). MS (ES+APCI) m/z=393(M+H).

Example 153N-(1-benzyl-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of lithium7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate

To a mixture of ethyl7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate(Preparation A; 0.239 g, 0.719 mmol) in THF (3 mL) was added H₂Ofollowed by LiOH (0.0344 g, 1.44 mmol) and the reaction was stirred atambient temperature overnight. The reaction was transferred to a sealedtube and heated to 100° C. for 8 hours. The reaction mixture wasconcentrated providing 0.230 g of the crude desired product as a paleyellow foam, which was used directly in the subsequent step.

Step B: Preparation ofN-(1-benzyl-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide

To a solution of lithium7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate(0.0585 g, 0.189 mmol) in CH₂Cl₂ was added a drop of DMF. Oxalylchloride (1.1 equivalents, 2M CH₂Cl₂) was added and the reaction stirredat ambient temperature until bubbling ceased (about 5 minutes).1-Benzyl-1H-indazol-4-amine (0.042 g, 0.189 mmol) was added followed byDIEA (1.2 equivalents). The reaction was stirred at ambient temperaturefor 4 hours. The reaction was concentrated and washed with Et₂O, water,and finally with Et₂O again. The pale yellow solid was dried, providing0.027 g of crude product. The crude material was purified using reversephase chromatography eluting with a gradient of 0 to 90% ACN/water togive 0.007 g (7%) of the desired product. MS (ES+APCI) m/z=510 (M+H).

Example 154N-(1-benzyl-1H-indazol-4-yl)-6-cyanoimidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 152, replacing7-cyanoimidazo[1,2-a]pyridine-3-carboxylic acid with6-cyanoimidazo[1,2-a]pyridine-3-carboxylic acid. MS (ES+APCI) m/z=393(M+H).

Example 155N-(1-benzyl-1H-indazol-4-yl)-6-bromoimidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 1-benzyl-4-nitro-1H-indazole

4-Nitro-1H-indazole (1.00 g; 6.13 mmol), benzyl bromide (1.15 g; 6.74mmol) and potassium carbonate (1.69 g; 12.3 mmol) were mixed with DMF(15 mL) and stirred at ambient temperature under nitrogen for 16 hours.The reaction mixture was added to water (50 mL) and extracted into ethylacetate. The combined extracted were dried (sodium sulfate), filteredand evaporated under reduced pressure to give a brown solid. Thematerial was purified by silica gel chromatography eluting withhexane/ethyl acetate (20:1 to 10:1 to 5:1). The first component to elutewas the desired regioisomer, which was obtained as a yellow solid (730mg). The other regioisomer was the second component to elute (650 mg).

Step B: Preparation of 1-benzyl-1H-indazol-4-amine

A mixture of 1-benzyl-4-nitro-1H-indazole (150 mg; 0.592 mmol), ironpowder (331 mg; 5.92 mmol) and ammonium chloride (16 mg; 0.296 mmol) inethanol/water (4:1; 5 mL) was heated at reflux for 5 hours. The solventwas removed under vacuum and the residue was mixed with ethylacetate/triethylamine (4:1; 5 mL) and heated at reflux for 1 hour. Themixture was allowed to cool and then filtered through a pad of silica,washing with ethyl acetate. The solvent was removed under vacuum to givethe desired product that was used directly in the next step.

Step C: Preparation of ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate

A mixture of 5-bromopyridin-2-amine (5.22 g, 30.2 mmol) and ethyl2-chloro-3-oxopropanoate (5.00 g, 33.2 mmol) (Toronto ResearchChemicals; 5% solution on benzene) was stirred in ethanol (151 mL, 30.2mmol) under nitrogen. The mixture was heated to 75° C. for 4 hours andthen at ambient temperature for 2 days. The solvent was removed undervacuum to give a solid residue which was purified by silica gelchromatography, eluting with hexane/ethyl acetate (6:4 to 4:6) to givethe desired product as a solid (2.40 g; 30%).

Step D: Preparation of 6-bromoimidazo[1,2-a]pyridine-3-carboxylic acid

Lithium hydroxide (0.427 g, 17.8 mmol) was added to a stirred suspensionof ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (2.40 g, 8.92 mmol)in 20 mL of a 4:1 mixture of THF/ethanol. The mixture was stirred undernitrogen for 3 days at ambient temperature. The pH of the mixture wasadjusted to neutral (by the addition of aqueous mineral acid) inducing aheavy precipitation of off-white colored solids. The solids wereisolated by filtration and dried under reduced pressure to give thedesired product (2.0 g; 93%).

Step E: Preparation ofN-(1-benzyl-1H-indazol-4-yl)-6-bromoimidazo[1,2-a]pyridine-3-carboxamide

6-Bromoimidazo[1,2-a]pyridine-3-carboxylic acid (200 mg; 0.83 mmol) wassuspended in methylene chloride (2 mL) with a catalytic (0.005 mL)amount of DMF. A solution of oxalyl chloride (0.913 mmol; 2M solution ondichloromethane) was added. The mixture was stirred in a sealed vial(with occasional venting to release gas) until effervescence ceased(about 30 minutes). A white suspension resulted. Diisopropylethylamine(188 μL; 1.08 mmol) was added. A clear solution resulted.1-Benzyl-1H-indazol-4-amine (185 mg; 0.83 mmol) was added as a solutionin methylene chloride followed by addition of furtherdiisopropylethylamine (188 L). The mixture was stirred at ambienttemperature for 24 hours. A suspension resulted. The mixture was dilutedwith ether (10 mL) and the solids were collected by filtration. Thefilter pad was washed with ether and water and the solids were driedunder vacuum to provide the desired product as a white solid (175 mg).MS (APCI) positive scan, m/z=446, 449 (M+H).

Example 156N-(1-benzyl-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 2-chloro-4-(2-methoxyethoxy)pyridine

A flask was charged with 2-chloro-4-nitropyridine (100 g, 630.7 mmol)and 2-methoxyethanol (746.8 mL, 9461 mmol) under an atmosphere of drynitrogen. The mixture was cooled with stirring to 0° C. utilizing anice/water bath. Potassium 2-methylpropan-2-olate (81.95 g, 693.8 mmol)was added and the mixture was stirred for 30 minutes. The ice/water bathwas removed and the mixture was stirred for an additional 2 hours atambient temperature. The mixture was concentrated under vacuum. Water(500 mL) was added and the mixture was extracted with dichloromethane.The combined extracts were dried over sodium sulfate, filtered andconcentrated under vacuum to give 2-chloro-4-(2-methoxyethoxy)pyridineas a gold colored oil (115 g).

Step B: Preparation of 4-(2-methoxyethoxy)pyridin-2-amine

2-Chloro-4-(2-methoxyethoxy)pyridine (30.0 g; 159.9 mmol), X-PHOS (3.03g, 6.356 mmol), and tris(dibenzylideneacetone)dipalladium (2.26 g; 2.468mmol) were combined in a reaction flask under an atmosphere of drynitrogen. Anhydrous tetrahydrofuran (150 mL) was added. The mixture wasdegassed by alternately evacuating the flask followed by filling withdry nitrogen (three times). The mixture was cooled to 0-5° C. using anice/water bath. LHMDS (325 mL, 325.0 mmol) was added by addition funnelwhile maintaining the temperature below 5° C. The ice/water bath wasremoved and the mixture was heated to reflux (60-65° C.) for 1.5 hours.After allowing the mixture to cool an ice/water bath was put in place.Hydrochloric acid (2N; 300 mL) was added with stirring, maintaining thetemperature below 30° C. After stirring for 15 minutes the mixture wastransferred to a separatory funnel with the addition of methyl t-butylether (300 mL) and water (20 mL). The phases were separated. The aqueousphase was basified by the addition of sodium hydroxide (50%; 10 mL) andthen extracted with dichloromethane. The combined dichloromethaneextracts were dried over sodium sulfate and filtered. Heptane (300 mL)was added. The solution was concentrated under vacuum to about one thirdthe initial volume. Heptane (200 mL) was added. Further concentrationresulted in solids precipitating. The solids were collected byfiltration and washed with heptane (100 mL). The solids were dried undervacuum at 55° C. to give 4-(2-methoxyethoxy)pyridin-2-amine as an offwhite solid (23.62 g).

Step C: Preparation of ethyl7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid

4-(2-Methoxyethoxy)pyridin-2-amine (5.00 g; 29.7 mmol) was mixed withethanol (20 mL) in a reaction flask, under an atmosphere of drynitrogen. A solution of ethyl 2-chloro-3-oxopropanoate (5% in benzene;110 mL; Commercial solution from Toronto Research Chemicals Inc.) wasadded. The mixture was heated to 60° C. under nitrogen for 4 hours.After allowing the mixture to cool the solvent was removed under vacuumto give a give a brown solid (9 g). The solid was mixed with ethylacetate (200 mL) and sodium bicarbonate solution (50 mL) and stirred todissolve. The phases were separated and the bicarbonate solution wasextracted with further ethyl acetate (50 mL). The combined ethyl acetateextracts were dried over sodium sulfate, filtered and concentrated undervacuum to give a brown solid (7.0 g). The material was dissolved inethyl acetate and passed through a short column of silica, eluting withethyl acetate. Factions containing product were concentrated to giveethyl 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylate as a creamcolored solid (3.77 g).

Step D: Preparation of7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid

Ethyl 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylate (6.06 g;22.9 mmol) was mixed with tetrahydrofuran (225 mL), ethanol (110 mL) andwater (55 mL). Lithium hydroxide monohydrate (0.962 g; 22.9 mmol) wasadded. The mixture was stirred under an atmosphere of nitrogen andheated at 40° C. for 22 hours. The mixture was allowed to cool and thenconcentrated under reduced pressure to give a yellow gum. Water (50 mL)was added and the mixture stirred to until homogeneous. Hydrochloricacid (2N) was added with stirring to adjust to pH 3. The mixture wascooled with an ice/water bath. The resulting precipitate was collectedby filtration and washed with a small amount of water (10 mL). Thematerial was dried under vacuum to give7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid as a whitesolid (4.90 g).

Step E: Preparation ofN-(1-benzyl-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide

To a suspension of7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (50 mg; 0.21mmol) in methylene chloride (2 mL) was added a catalytic (0.005 mL)amount of DMF followed by oxalyl chloride (0.23 mmol; 2M solution inmethylene chloride). The mixture was stirred in a sealed vial untileffervescence ceased (approximately 30 minutes), with occasional ventingto release gas. 1-Benzyl-1H-indazol-4-amine (Example 155, Steps A-B; 47mg; 0.21 mmol) was added as a solution in methylene chloride (1 mL)followed by diisopropylethylamine (33 mg; 0.25 mmol). The mixture wasstirred for 16 hours at ambient temperature, during which time asuspension formed. The mixture was partitioned between water andmethylene chloride and the suspension was extracted multiple times withmethylene chloride. The combined organic phases (which containedsuspended solids) were concentrated under reduced pressure. Theresulting solid material was triturated with ether and collected byfiltration. The solids were washed with ether, water and then etheragain. The material was dried under vacuum to give an off white solid(67 mg). MS (APCI), m/z=442.2 (M+H).

Example 157N-(1-benzyl-1H-indazol-4-yl)-7-(1,2-dihydroxyethyl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of ethyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate

4-bromopyridin-2-amine (10.0 g, 0.06 mol) was mixed with ethanol (50 mL)in a reaction flask, under an atmosphere of dry nitrogen. A solution ofethyl 2-chloro-3-oxopropanoate (5% in benzene; 222 mL; Commercialsolution from Toronto Research Chemicals Inc.) was added. The mixturewas heated to 60° C. under nitrogen for 5 hours. After allowing themixture to cool the solvent was removed under vacuum to give a brownsolid. The solid was mixed with ethyl acetate (500 mL) and sodiumbicarbonate solution (200 mL) and stirred to dissolve. The phases wereseparated and the bicarbonate solution was extracted further with ethylacetate (100 mL). The combined ethyl acetate extracts were dried oversodium sulfate, filtered and concentrated under vacuum to give a solid.The crude material was dissolved in ethyl acetate and passed through ashort column of silica, eluting with ethyl acetate to give ethyl7-bromoimidazo[1,2-a]pyridine-3-carboxylate as a pale yellow solid (15g).

Step B: Preparation of 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid

Added ethyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate (15 g, 56 mmol)and lithium hydroxide monohydrate (3 g, 71.4 mmol) intotetrahydrofuran/ethanol/water (1:2:1, 560 mL total) solution. Afterstirring at ambient temperature overnight, the solvent was removed undervacuum to give a yellow gum. Water (300 mL) and dichloromethane wasadded, and the phases were separated. The aqueous layer was cooled in anice-water bath before adjusting the pH to 3 using 2N sulfuric acid. Theproduct precipitated out and was collected by filtration and washed witha small amount of water (50 mL) before drying under vacuum to give7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid as an off-white solid(8.3 g).

Step C: Preparation ofN-(1-benzyl-1H-indazol-4-yl)-7-bromoimidazo[1,2-a]pyridine-3-carboxamide

To a solution of 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (42 mg;0.17 mmol) in dichloromethane (1 mL) was added oxalyl chloride (1.1equivalents; 2M solution in dichloromethane) followed by a catalyticamount of DMF. The mixture was stirred in a sealed container stirreduntil effervescence stopped, venting occasionally to release gas.1-Benzyl-1H-indazol-4-amine (Example 155, Steps A-B; 39 mg; 0.17 mmol)was added followed by diisopropylethylamine (2 equivalents). The mixturewas stirred at ambient temperature for 2 days. The mixture was dilutedwith methanol and the solids were collected by filtration and washedtwice with 2M aqueous sodium carbonate solution, water and ether. Thesolids were then dried to give the desired product as an off-white solid(53 mg).

Step D: Preparation ofN-(1-benzyl-1H-indazol-4-yl)-7-vinylimidazo[1,2-a]pyridine-3-carboxamide

A mixture ofN-(1-benzyl-1H-indazol-4-yl)-7-bromoimidazo[1,2-a]pyridine-3-carboxamide(50 mg; 0.112 mmol), tributylvinyltin (43 mg; 0.13 mmol) and cesiumfluoride (34 mg; 0.22 mmol) were mixed with DMF (1 mL) under nitrogen.Palladium (II) chloride (0.8 mg; 0.005 mmol), tri-tert-butylphosphine(18 mg; 0.009 mmol) and copper (I) iodide (1.7 mg; 0.009 mmol) wereadded and the mixture was purged with nitrogen and then heated in asealed vessel at 45° C. for 16 hours. The mixture was added to water (30mL) and extracted into ethyl acetate. The combined extracts were washedwith water, dried (sodium sulfate) and filtered through a pad of silica.The solvent was removed under vacuum to provide a white solid which wastriturated with ether to provide the desired product (27 mg) ofsufficient purity to take to the next step.

Step E: Preparation ofN-(1-benzyl-1H-indazol-4-yl)-7-(1,2-dihydroxyethyl)imidazo[1,2-a]pyridine-3-carboxamide

To a solution ofN-(1-benzyl-1H-indazol-4-yl)-7-vinylimidazo[1,2-a]pyridine-3-carboxamide(27 mg; 0.069 mmol) in acetone/water (3:2; 1 mL) were added osmiumtetroxide (0.1 equivalents as a 2% solution in t-butanol) andN-methylmorpholine N-oxide (1.2 equivalents as a 50% solution on water).The mixture was stirred at ambient temperature for several days. Furtheraliquots of osmium tetroxide and N-methyl morpholine N-oxide were addedat intervals until the reaction was complete by LC. The mixture added towater and extracted into ethyl acetate. Some insoluble material wasisolated by filtration. The extracts were combined, concentrated undervacuum and combined with the solids isolated by filtration. The combinedmaterial was purified by preparative thin layer chromatography onsilica, eluting with dichloromethane/ethanol/ammonium hydroxide(100:20:0.5) to give the desired product (2.6 mg). MS (APCI), m/z=428.2(M+H).

Example 158N-(1-benzyl-1H-indazol-4-yl)-6-(1,2-dihydroxyethyl)imidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation ofN-(1-benzyl-1H-indazol-4-yl)-6-vinylimidazo[1,2-a]pyridine-3-carboxamide

A mixture ofN-(1-benzyl-1H-indazol-4-yl)-6-bromoimidazo[1,2-a]pyridine-3-carboxamide(Example 155; 75 mg; 0.168 mmol), tributyl(vinyl)stannane (59 mg; 0.185mmol), tris(dibenzylideneacetone)dipalladium(0) (2.3 mg; 0.0025 mmol),bis(tri-tert-butylphosphine)palladium(0) (2.6 mg; 0.0050 mmol) andcesium fluoride (56 mg; 0.37 mmol) in NMP was stirred under nitrogen at60° C. for 5 hours. Additional amounts of the palladium catalysts andthe tributyl(vinyl)tin (similar quantities to those added initially)were added and the mixture was heated for an additional 12 hours. Themixture was added to water (20 mL) and extracted into ethyl acetate. Thecombined extracts were washed with water and brine and dried (sodiumsulfate). The filtered solution was concentrated under reduced pressure.The material was purified by silica gel chromatography, eluting withethyl acetate, to provide the desired product as an oil (66 mg) whichsolidified on standing.

Step B: Preparation ofN-(1-benzyl-1H-indazol-4-yl)-6-(1,2-dihydroxyethyl)imidazo[1,2-a]pyridine-3-carboxamide

A mixture ofN-(1-benzyl-1H-indazol-4-yl)-6-vinylimidazo[1,2-a]pyridine-3-carboxamide(63 mg; 0.16 mmol), osmium tetroxide (0.008 mmol; 2.5% solution int-butanol) and N-methylmorpholine N-oxide (21 mg; 0.18 mmol) inacetone/water (3:2; 1 mL) was stirred at ambient temperature for 24hours. Additional osmium tetroxide was added (250 μL of a 2.5% solutionin t-butanol) and the mixture was stirred for an additional 24 hours.The mixture was diluted with ethyl acetate and solids were isolated byfiltration. The material was purified by reverse phase chromatography(acetonitrile/water) to give the desired product as a solid (3.6 mg). MS(APCI), m/z=428.2 (M+H).

Example 159N-(1-benzyl-1H-indazol-4-yl)-6-methoxyimidazo[1,2-a]pyridine-3-carboxamide

Step A: Preparation of 6-methoxyimidazo[1,2-a]pyridine-3-carboxylic acid

Prepared according to the method of Example 152, Steps A-B replacing2-aminoisonicotinonitrile with 5-methoxypyridin-2-amine.

Step B: Preparation of 1-benzyl-4-nitro-1H-indazole

To a solution of 4-nitro-1H-indazole (0.500 g, 3.06 mmol) in acetone(0.4M, 7.5 mL) cooled to 0° C. was added KOH (0.258 g, 4.60 mmol). After15 minutes at 0° C., (bromomethyl)benzene (0.400 mL, 3.37 mmol) wasadded. The reaction mixture was allowed to stir at ambient temperatureovernight. The reaction mixture was concentrated under reduced pressureand the residue was purified by column chromatography (50%EtOAc/hexanes) providing 256 mg (33%) of the title compound.

Step C: Preparation of 1-benzyl-1H-indazol-4-amine

1-Benzyl-4-nitro-1H-indazole (672 mg, 2.65 mmol) was taken up in 26 mLof EtOH/water (4:1) and treated with NH4Cl (0.5 equivalents) and Fepowder (10 equivalents). The reaction was heated to reflux for 2 hours.The reaction was concentrated under reduced pressure, diluted withEtOAc:Et₃N (4:1) and stirred for two hours. The reaction mixture wasfiltered over GF/F paper and concentrated to give a brown, viscous oil.This crude material was purified by column chromatography (30%EtOAc/hexanes) providing 363 mg (61%) of the title compound.

Step D: Preparation ofN-(1-benzyl-1H-indazol-4-yl)-6-methoxyimidazo[1,2-a]pyridine-3-carboxamide

6-Methoxyimidazo[1,2-a]pyridine-3-carboxylic acid (29.5 mg, 0.154 mmol)was taken up in DCM. Oxalyl chloride (1.1 equivalents) was addedfollowed by a drop of DMF. The reaction was stirred at ambienttemperature until bubbling ceased, and then 1-benzyl-1H-indazol-4-amine(34.3 mg, 0.154 mmol) was added followed by DIEA (1.2 equivalents). Thereaction was stirred at ambient temperature overnight. The reaction wasconcentrated, triturated with ether and purified by Preparative TLC (1mm) eluting with 10% MeOH/DCM to give 15 mg (25%) of the desiredproduct. MS (ES+APCI) m/z=398.3 (M+H).

Example 160 Preparation ofN3-(1-benzyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3,6-dicarboxamide

Prepared according to the method of Example 159, replacing6-methoxyimidazo[1,2-a]pyridine-3-carboxylic acid with6-carbamoylimidazo[1,2-a]pyridine-3-carboxylic acid. MS (ES+APCI)m/z=411.3 (M+H).

Example 161N-(1-benzyl-1H-indazol-4-yl)-7-bromoimidazo[1,2-a]pyridine-3-carboxamide

Prepared according to the method of Example 159, replacing6-methoxyimidazo[1,2-a]pyridine-3-carboxylic acid with7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid.

1-29. (canceled)
 30. A compound having the general formula IV

wherein: X¹ is F or Cl, R¹ is hetAr¹(CH₂)_(m)—, hetAr²CH₂—, hetAr³CH₂—,(3-6C cycloalkyl)-CH₂—, hetCyc¹CH₂—, Ar¹(CH₂)_(n)— or (N-1-3Calkyl)pyridinonyl-CH₂—; hetAr¹ is a 6-membered heteroaryl having 1-2ring N atoms and optionally substituted with one or more substituentsindependently selected from (1-6C)alkyl, (1-4C)alkoxy, halogen, CF₃, or(3-6C)cycloalkyl; m is 0, 1 or 2; hetAr² is a 5-membered heteroaryl ringhaving 2-3 ring heteroatoms independently selected from N and S where atleast one of said heteroatoms is N, wherein said ring is optionallysubstituted with one or more substituents independently selected from(1-6C)alkyl; hetAr³ is a bicyclic 5,6-fused heteroaryl ring having tworing nitrogen atoms; hetCyc¹ is a 6-membered saturated heterocyclic ringhaving 1-2 ring heteroatoms independently selected from N and O andoptionally substituted with —C(═O)(1-6C alkyl) or —C(═O)O(1-6C alkyl);Ar¹ is phenyl optionally substituted with one or more substituentsindependently selected from halogen, (1-6C)alkyl, CN, CF₃, OH,(1-6C)alkoxy, —C(═O)OH, —C(═O)O(1-6C alkyl), —C(═O)NR^(a)R^(b) orbenzyloxy; R^(a) and R^(b) are independently H or (1-6C)alkyl; n is 0, 1or 2; R² is H, F, Cl or CH₃; R³ is H, F or Cl; and R⁴ is H, CN, F, Cl,Br, —OMe, —OCF₃, —CF₃, —CH(OH)CH₂OH or —C(═O)NH₂.
 31. A compound ofclaim 30, wherein R¹ is hetAr¹(CH₂)_(m)—, hetAr²CH₂— or hetAr³CH₂.
 32. Acompound according to claim 30, wherein R¹ is hetAr¹(CH₂)_(m)—.
 33. Acompound according to claim 30, wherein m is
 1. 34. A compound accordingto claim 30, wherein R² is H.
 35. A compound according to claim 30,wherein R² is F or Cl.
 36. A compound according to claim 30, wherein R²is CH₃.
 37. A compound according to claim 30, wherein R³ is H.
 38. Acompound according to claim 30, wherein R³ is F or Cl.
 39. A compoundaccording to claim 30, wherein R⁴ is H.
 40. A compound according toclaim 30, wherein R⁴ is CN, Br, —OMe, —CH(OH)CH₂OH or —C(═O)NH₂.
 41. Acompound according to claim 30, wherein X¹ is F.
 42. A compoundaccording to claim 30, wherein X¹ is Cl.
 43. A compound according toclaim 30, wherein: R¹ is hetAr¹(CH₂)_(m)—, hetAr²CH₂— or hetAr³CH₂—; mis 1; R² is H or CH₃; R³ is H; and R⁴ is H.
 44. A compound according toclaim 43, wherein R² is H.
 45. A compound according to claim 44, whereinR¹ is hetAr¹(CH₂)_(m)—.
 46. A compound according to claim 45, wherein X¹is F.
 47. A compound according to claim 45, wherein X¹ is Cl.
 48. Acompound according to claim 43, wherein R² is CH₃.
 49. A compoundaccording to claim 48, wherein R¹ is hetAr¹(CH₂)_(m)—.
 50. A compoundaccording to claim 49, wherein X¹ is F.
 51. A compound according toclaim 49, wherein X¹ is Cl.